(R)-Chiral halogenated substituted fused heterocyclic amino compounds useful for inhibiting cholesteryl ester transfer protein activity

ABSTRACT

The invention relates to substituted aryl and heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanol compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-l) and compounds, compositions and methods for treating atherosclerosis and other coronary artery diseases. Novel high yield, stereoselective processes for the preparation of the chiral substituted alkanol compounds from chiral and achiral intermediates are described. Preferred (R)-Chiral 1-Substitutedamino-(n+1)-Alkanol compounds are substituted (R)-Chiral fused heterocyclic amino compounds. A preferred specific (R)-Chiral fused heterocyclic amino compound is:

FIELD OF THE INVENTION

[0001] This invention is in the field of treating cardiovasculardisease, and specifically relates to compounds, compositions, methodsfor treating atherosclerosis and other coronary artery disease, andmethods for making compounds of this invention. More particularly, theinvention relates to (R)-chiral halogenated1-substitutedamino-(n+1)-alkanol compounds that inhibit cholesterylester transfer protein (CETP), also known as plasma lipid transferprotein-I.

BACKGROUND OF THE INVENTION

[0002] Numerous studies have demonstrated that a low plasmaconcentration of high density lipoprotein (HDL) cholesterol is apowerful risk factor for the development of atherosclerosis (Barter andRye, Atherosclerosis, 121, 1-12 (1996)). HDL is one of the major classesof lipoproteins that function in the transport of lipids through theblood. The major lipids found associated with HDL include cholesterol,cholesteryl ester, triglycerides, phospholipids and fatty acids. Theother classes of lipoproteins found in the blood are low densitylipoprotein (LDL) and very low density lipoprotein (VLDL). Since lowlevels of HDL cholesterol increase the risk of atherosclerosis, methodsfor elevating plasma HDL cholesterol would be therapeutically beneficialfor the treatment of atherosclerosis and other diseases associated withaccumulation of lipid in the blood vessels. These diseases include, butare not limited to, coronary heart disease, peripheral vascular disease,and stroke.

[0003] Atherosclerosis underlies most coronary artery disease (CAD), amajor cause of morbidity and mortality in modern society. High LDLcholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl)have been shown to be important contributors to the development ofatherosclerosis. Other diseases, such as peripheral vascular disease,stroke, and hypercholesterolaemia are negatively affected by adverseHDL/LDL ratios. Inhibition of CETP by the subject compounds is shown toeffectively modify plasma HDL/LDL ratios, and to check the progressand/or formation of these diseases.

[0004] CETP is a plasma protein that facilitates the movement ofcholesteryl esters and triglycerides between the various lipoproteins inthe blood (Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement ofcholesteryl ester from HDL to LDL by CETP has the effect of lowering HDLcholesterol. It therefore follows that inhibition of CEIP should lead toelevation of plasma HDL cholesterol and lowering of plasma LDLcholesterol, thereby providing a therapeutically beneficial plasma lipidprofile (McCarthy, Medicinal Res. Revs., 13, 139-59 (1993); Sitori,Pharmac. Ther., 67,443-47 (1995)). This exact phenomenon was firstdemonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) withthe use of a monoclonal antibody that specifically inhibited CERP. Inrabbits, the antibody caused an elevation of the plasma HDL cholesteroland a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta795, 743480 (1984)), Morton et al. (J. Lipid Res. 35, 836-847 (1994))and Tollefson et al. (Am. J. Physiol., 255, (Endocrinol. Metab. 18,E894E902 (1988))) describe proteins from human plasma that inhibit CERP.U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 aminoacid peptide derived from baboon apo C-1 that inhibits CERP activity.Cho et al. (Biochim. Biophys. Acta 1391, 133-144 (1998)) describe apeptide from hog plasma that inhibits human CETP. Bonin et al. (J.Peptide Res., 51, 216-225 (1998)) disclose a decapeptide inhibitor ofCETP. A depsipeptide fungal metabolite is disclosed as a CETP inhibitorby Hedge et al. in Bioorg. Med. Chem. Lett., 8, 1277-80 (1998).

[0005] There have been several reports of non-peptidic compounds thatact as CETP inhibitors. Barrett et al. (J. Am. Chem. Soc., 188, 7863-63(1996)) and Kuo et al. (J. Am. Chem. Soc., 117, 10629-34 (1995))describe cyclopropane-containing CERP inhibitors. Pietzonka et al.(Bioorg. Med. Chem. Lett, 6, 1951-54 (1996)) describephosphonate-containing analogs of cholesteryl ester as CETP inhibitors.Coval et al. (Bioorg. Med. Chem. Lett., 5, 605-610 (1995)) describeWiedendiol-A and -B, and related sesquiterpene compounds as CETPinhibitors. Japanese Patent Application No. 10287662-A describespolycyclic, non-amine containing, polyhydroxylic natural compoundspossessing CETP inhibition properties. Lee et al. (J. Antibiotics, 49,693-96 (1996)) describe CETP inhibitors derived from an insect fungus.Busch et al. (Lipids, 25, 216-220, (1990)) describe cholesteryl acetylbromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35,83647 (1982)) describe that p-chloromercuriphenyl sulfonate,p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP.Connolly et al. (Biochem. Biophys. Res. Comm. 223, 4247 (1996)) describeother cysteine modification reagents as CETP inhibitors. Xia et al.describe 1,3,5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett.,6, 919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994)) describe4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor. Oomuraet al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETPinhibitors in Japanese Patent Application No. 10287662.

[0006] Some substituted heteroalkylamine compounds are known. InEuropean Patent Application No. 796846, Schmidt et al. describe2-aryl-substituted pyridines as cholesteryl ester transfer proteininhibitors useful as cardiovascular agents. One substitutent at C3 ofthe pyridine ring can be an hydroxyalkyl group. In European PatentApplication No. 801060, Dow and Wright describe heterocyclic derivativessubstituted with an aldehyde addition product of an alkylamine to afford1-hydroxy-1-amines. These are reported to be β3-adrenergic receptoragonists useful for treating diabetes and other disorders. In GreatBritain Patent Application No. 2305665, Fisher et al. disclose 3-agonistsecondary amino alcohol substituted pyridine derivatives useful fortreating several disorders including cholesterol levels andartherosclerotic diseases. In European Patent Application No. 818448,Schmidt et al. describe tetrahydroquinoline derivatives as cholesterylester transfer protein inhibitors. European Patent Application No.818197, Schmek et al. describe pyridines with fused heterocycles ascholesteryl ester transfer protein inhibitors. Brandes et al. in GermanPatent Application No. 19627430 describe bicyclic condensed pyridinederivatives as cholesteryl ester transfer protein inhibitors. In WOPatent Application No. 09839299, Muller-Gliemann et al. describequinoline derivatives as cholesteryl ester transfer protein inhibitors.U.S. Pat. No. 2,700,686, issued to Dickey and Towne, describesN-(2-haloalkyl-2-hydroxyethyl)amines in which the amine is furthersubstituted with either 1 to 2 aliphatic groups or one aromatic groupand one aliphatic group. U.S. Pat. No. 2,700,686 further describes aprocess to prepare the N-(2-haloalkyl-2-hydroxyethyl)amines by reactinghalogenated-1,2-epoxyalkanes with the corresponding aliphatic amines andN-alkylanilines and their use as dye intermediates.

SUMMARY OF THE INVENTION

[0007] The present invention provides chiral compounds that can be usedto inhibit cholesteryl ester transfer protein (CEFP) activity and thathave the general structure:

[0008] In another aspect, the present invention includes pharmaceuticalcompositions comprising a pharmaceutically effective amount of thechiral compounds of this invention and a pharmaceutically acceptablecarrier.

[0009] In another aspect, this invention relates to methods of usingthese chiral inhibitors as therapeutic agents in humans to inhibitcholesteryl ester transfer protein (CETP) activity, thereby decreasingthe concentrations of low density lipoprotein (LDL) and raising thelevel of high density lipoprotein (HDL), resulting in a therapeuticallybeneficial plasma lipid profile. The compounds and methods of thisinvention can also be used to treat dyslipidemia(hypoalphalipoproteinemia), hyperlipoproteinaemia (chylomicronemia andhyperapobetalipoproteinemia), peripheral vascular disease,hypercholesterolaemia, atherosclerosis, coronary artery disease andother CETP-mediated disorders. The compounds can also be used inprophylactic treatment of subjects who are at risk of developing suchdisorders. The compounds can be used to lower the risk ofatherosclerosis. The compounds of this invention would be also useful inprevention of cerebral vascular accident (CVA) or stroke. Besides beinguseful for human treatment, these compounds are also useful forveterinary treatment of companion animals, exotic animals and farmanimals such as primates, rabbits, pigs, horses, and the like.

DESCRIPTION OF THE INVENTION

[0010] The present invention relates to a class of compounds comprising(R)-chiral halogenated 1-substitutedamino-(n+1)-alkanols which arebeneficial in the therapeutic and prophylactic treatment of coronaryartery disease as given in Formula I-H (also referred to herein asgeneric polycyclic aryl and heteroaryl (R)-chiral halogenated1-substitutedamino-(n+1)-alkanols):

[0011] or a pharmaceutically-acceptable salt thereof, wherein;

[0012] n is an integer selected from 1 through 4;

[0013] X is oxy;

[0014] R₁ is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R₁ has a higher Cahn-Ingold-Prelog stereochemical system rankingthan both R₂ and (CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q isFormula (III);

[0015] R₁₆ is selected from the group consisting of hydrido, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl,monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl,dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacerselected from the group consisting of a covalent single bond and alinear spacer moiety having a chain length of 1 to 4 atoms linked to thepoint of bonding of any aromatic substituent selected from the groupconsisting of R₄, R₈, R₉, R₁₃, R₁₄, and R₁₅ to form a heterocyclyl ringhaving from 5 through 10 contiguous members;

[0016] D₁, D₂, J₁, J₂ and K₁ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that nomore than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, no morethan one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁, D₂,J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalentbond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more thanfour of D₁, D₂, J₁, J₂ and K₁ can be N;

[0017] D₃, D₄, J₃, J₄ and K₂ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that nomore than one can be a covalent bond, no more than one of D₃, D₄, J₃, J₄and K₂ can be O, no more than one of D₃, D₄, J₃, J₄ and K₂ can be S, nomore than two of D₃, D₄, J₃, J₄ and K₂ can be O and S, one of D₃, D₄,J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂are O and S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

[0018] R₂ is hydrido;

[0019] R₂ can be selected from the group consisting of hydroxyalkyl,alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, perhaloaryl, perhaloaralkyl, perhaloaralkyl,heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dicyanoalkyl, carboalkoxycyanoalkyl,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(A)Q;

[0020] R₃ is selected from the group consisting of hydrido, hydroxy,halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino,acyl, acylamido, alkoxy, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl withthe provisos that (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂;

[0021] Y is selected from a group consisting of a covalent single bond,(C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2 and(CH(R₁₄))_(g)—W—(CH(R₁₄))_(p) wherein g and p are integers independentlyselected from 0 through 1;

[0022] R₁₄ is independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R₉ and R₁₃ to form a ringselected from the group consisting of a cycloalkenyl ring having from 5through 8 contiguous members and a heterocyclyl ring having from 5through 8 contiguous members, and a spacer selected from a moiety havinga chain length of 2 to 5 atoms connected to the point of bondingselected from the group consisting of R₄ and R₈ to form a heterocyclylhaving from 5 through 8 contiguous members with the proviso that, when Yis a covalent bond, an R₁₄ substituent is not attached to Y;

[0023] R₁₄ and R₁₅ can be taken together to form a spacer selected froma moiety having a chain length of 2 to 5 atoms to form a heterocyclylring having from 5 through 8 contiguous members;

[0024] R₁₄ and R₁₄, when bonded to the different atoms, can be takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

[0025] R₁₄ and R₁₄, when bonded to the same atom can be taken togetherto form a group selected from the group consisting of oxo, thiono,alkylene, haloalkylene, and a spacer selected from the group consistingof a moiety having a chain length of 3 to 7 atoms connected to form aring selected from the group consisting of a cycloalkyl having from 4through 8 contiguous members, a cycloalkenyl having from 4 through 8contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0026] W is selected from the group consisting of O, C(O), C(S),C(O)N(R₁₄, C(S)N(R₁₄), (R₁₄NC(O), (R₁₄)NC(S), S, S(O), S(O)₂,S(O)₂N(R₁₄), (R₁₄)NS(O)₂, and N(R₁₄) with the proviso that R₁₄ isselected from other than halo and cyano;

[0027] Z is independently selected from a group consisting of a covalentsingle bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1through 2, (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integersindependently selected from 0 through 1 with the proviso that, when Z isa covalent single bond, an R₁₅ substituent is not attached to Z;

[0028] R₁₅ is independently selected, when Z is (C(R₁₅)₂)_(q) wherein qis an integer selected from 1 through 2, from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R₄ and R₈ to form a ringselected from the group consisting of a cycloalkenyl ring having from 5through 8 contiguous members and a heterocyclyl ring having from 5through 8 contiguous members, and a spacer selected from a moiety havinga chain length of 2 to 5 atoms connected to the point of bondingselected from the group consisting of R₉ and R₁₃ to form a heterocyclylhaving from 5 through 8 contiguous members;

[0029] R₁₅ and R₁₅, when bonded to the different atoms, can be takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

[0030] R₁₅ and R₁₅, when bonded to the same atom, can be taken togetherto form a group selected from the group consisting of oxo, thiono,alkylene, haloalkylene, and a spacer selected from the group consistingof a moiety having a chain length of 3 to 7 atoms connected to form aring selected from the group consisting of a cycloalkyl having from 4through 8 contiguous members, a cycloalkenyl having from 4 through 8contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0031] R₁₅ is independently selected, when Z is(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 1, from the group consisting of hydrido, halo,cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl,heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl,alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, talocalkyl,halcyalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R₄ and R₈ to forma ring selected from the group consisting of a cycloalkenyl ring havingfrom 5 through 8 contiguous members and a heterocyclyl ring having from5 through 8 contiguous members, and a spacer selected from a linearmoiety having a chain length of 2 to atoms connected to the point ofbonding selected from the group consisting of R₉ and R₁₃ to form aheterocyclyl ring having from 5 through 8 contiguous members;

[0032] R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl,heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamnino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R₄, R₅, R₆, R₇, and R₈ present, that thereare one to five non-hydrido ring substituents R₉, R₁₀, R₁₁, R₁₂, and R₁₃present, and R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are eachindependently selected to maintain the tetravalent nature of carbon,trivalent nature of nitrogen, the divalent nature of sulfur, and thedivalent nature of oxygen;

[0033] R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ andR₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be independently selected to formspacer pairs wherein a spacer pair is taken together to form a linearmoiety having from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇and R₈, can be used at the same time and that no more than one of thegroup consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂,and R₁₂ and R₁₃ can be used at the same time;

[0034] R₄ and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ can beindependently selected to form a spacer pair wherein said spacer pair istaken together to form a linear moiety wherein said linear moiety formsa ring selected from the group consisting of a partially saturatedheterocyclyl ring having from 5 through 8 contiguous members and aheteroaryl ring having from 5 through 6 contiguous members with theproviso that no more than one of the group consisting of spacer pairs R₄and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ can be used at the sametime;

[0035] R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ can beindependently selected to form a spacer pair wherein said spacer pair istaken together to form a linear moiety wherein said linear moiety formsa C8 to C13 heterocyclyl ring having from 8 through 13 contiguousmembers with the proviso that no more than one of the group consistingof spacer pairs R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ canbe used at the same time.

[0036] In a another embodiment of compounds of Formula I-H,

[0037] D₁, D₂, J₁, J₂ and K₁ are each carbon with the proviso that atleast one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consistingof O, S, and N, wherein D₃, D₄, J₃, J₄ and K₂ are independently selectedfrom the group consisting of C, N, O, S and covalent bond with theprovisos that no more than one of D₃, D₄, J₃, J₄ and K₂ can be acovalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, nomore than one of D₃, D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are Oand S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

[0038] D₁, D₂, J₁, J₂ and K₁ can be selected from the group consistingof C, O, S, N and covalent bond with the provisos that D₃, D₄, J₃, J₄and K₂ are each carbon and at least one of D₁, D₂, J₁, J₂ and K₁ isselected from the group consisting of O, S, and N wherein, when D₁, D₂,J₁, J₂ and K₁ are selected from the group consisting of C, O, S,covalent bond, and N, no more than one of D₁, D₂, J₁, J₂ and K₁ can be acovalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, nomore than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are Oand S, and no more than four of D₁, D₂, J₁, J₂ and K₁ can be N;

[0039] n is an integer selected from 1 through 4;

[0040] X is oxy;

[0041] R₁₆ is selected from the group consisting of hydrido, acyl,aroyl, and trialkylsilyl;

[0042] R₁ is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R₁ has a higher Cahn-Ingold-Prelog stereochemical system rankingthan both R₂ and (CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q isFormula (III),

[0043] R₂ is hydrido;

[0044] R₂ can be selected from the group consisting of aryl, aralkyl,alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl,heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(A)Q;

[0045] R₃ is selected from the group consisting of hydrido, hydroxy,cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl,heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl,carboxamide, and carboxamidoalkyl with the provisos that(CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelog stereochemical systemranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical systemranking than R₂;

[0046] Y is selected from the group consisting of covalent single bondand (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

[0047] R₁₄ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

[0048] Z is selected from the group consisting of covalent single bond,(C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 1;

[0049] W is oxy;

[0050] R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

[0051] R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido, halo, haloalkyl, and alkyl;

[0052] R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio,heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro,lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio,arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl,arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio,alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo,haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aryloxy,aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy,heteroaryloxyalkyl, heteroaralkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;

[0053] R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ anR₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independentlyselected from the group consisting of alkylene, alkenylene,alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene withthe provisos that no more than one of the group consisting of spacerpairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈ can be used at thesame time and that no more than one of the group consisting of spacerpairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be usedat the same time.

[0054] In an even more specific embodiment of compounds Formula I-H,

[0055] D₁, D₂, J₁, J₂ and K₁ are each carbon;

[0056] D₃, D₄, J₃, J₄ and K₂ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that atleast one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consistingof O, S, and N, wherein no more than one of D₃, D₄, J₃, J₄ and K₂ can bea covalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, nomore than one of D₃, D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are Oand S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

[0057] n is an integer selected from 1 to 3;

[0058] X is oxy;

[0059] R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

[0060] R₁₆ is selected from the group consisting of acetyl, benzoyl,dimethyl tert-butylsilyl, hydrido, and trimethylsilyl;

[0061] R₂ is hydrido;

[0062] R₂ can be selected from the group consisting of hydrido, methyl,ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl,4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl,trifluoromethoxymethyl, fluoromethyl, difluoromethyl,2,2,3,3,3-pentafluoropropyl, and pentafluorophenoxymethyl with theproviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than bothR₁ and (CHR₃)_(n)—N(A)Q;

[0063] R₃ is selected from the group consisting of hydrido, hydroxy,cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl,methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, andpentafluorophenoxymethyl with the provisos that (CHR₃)_(n)—N(A)Q has alower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and ahigher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

[0064] In another even more specific embodiment of compounds FormulaI-H,

[0065] D₃, D₄, J₃, J₄ and K₂ are each carbon;

[0066] D₁, D₂, J₁, J₂ and K₁ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that atleast one of D₁, D₂, J₁, J₂ and K₁ is selected from the group consistingof O, S, and N, wherein no more than one of D₁, D₂, J₁, J₂ and K₁ can bea covalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, nomore than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂and K, must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are Oand S, and no more than four of D₁, D₂, J₁, J₂ and K₁ can be N;

[0067] n is an integer selected from 1 to 3;

[0068] X is oxy;

[0069] R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

[0070] R₁₆ is selected from the group consisting of acetyl, benzoyl,dimethyl tert-butylsilyl, hydrido, and trimethylsilyl;

[0071] R₂ is hydrido;

[0072] R₂ can be selected from the group consisting of hydrido, methyl,ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl,4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl,trifluoromethoxymethyl, fluoromethyl, difluoromethyl,2,2,3,3,3-pentafluoropropyl, and pentafluorophenoxymethyl with theproviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than bothR₁ and (CHR₃)_(n)—N(A)Q;

[0073] R₃ is selected from the group consisting of hydrido, hydroxy,cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl,methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, andpentafluorophenoxymethyl with the provisos that (CHR₃)_(n)—N(A)Q has alower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and ahigher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

[0074] In a preferred embodiment of compounds of Formula I-H, thecompounds correspond to the Formula I-C (also referred to herein asphenyl (R)-chiral halogenated 1-substitutedamino-(n+1)-alkanols):

[0075] or a pharmacuetically acceptable salt thereof, wherein;

[0076] n is an integer selected from 1 through 4;

[0077] R₁₆ is selected from the group consisting of hydrido, alkyl,acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from thegroup consisting of a covalent single bond and a linear spacer moietyhaving a chain length of 1 to 4 atoms linked to the point of bonding ofany aromatic substituent selected from the group consisting of R₄, R₈,R₉, and R₁₃ to form a heterocyclyl ring having from 5 through 10contiguous members with the proviso that said linear spacer moiety isother than covalent single bond when R₂ is alkyl;

[0078] R₁ is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R₁ has a higher Cahn-Ingold-Prelog stereochemical system rankingthan both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qpis Formula (III-P);

[0079] R₂ is hydrido;

[0080] R₂ can be selected from the group consisting of aryl, aralkyl,alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl,heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(Ap)Qp;

[0081] R₃ is selected from the group consisting of hydrido, hydroxy,cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl,heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl,carboxamide, and carboxamidoalkyl with the provisos that(CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical systemranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical systemranking than R₂;

[0082] Y is selected from the group consisting of covalent single bondand (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

[0083] R₁₄ is selected from the group consisting of hydrido, hydroxy,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;

[0084] Z is selected from the group consisting of covalent single bond,(C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 1;

[0085] W is selected from the group consisting of O, C(O), C(S),C(O)N(R₁₄), C(S)N(R₁₄), (R₁₄)NC(O), (R₁₄)NC(S), S, S(O), S(O)₂,S(O)₂N(R₁₄), (R₁₄)NS(O)₂, and N(R₁₄) with the proviso that R₁₄ is otherthan cyano;

[0086] R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0087] R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido, halo, haloalkyl, and alkyl;

[0088] R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy,cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy,aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl,perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl,heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl;

[0089] R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀andR₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be independently selected to formspacer pairs wherein a spacer pair is taken together to form a linearmoiety having from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇and R₈, can be used at the same time and that no more than one of thegroup consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂,and R₁₂ and R₁₃ can be used at the same time.

[0090] In a preferred embodiment of compounds of Formula I-C,

[0091] n is an integer selected from 1 through 4;

[0092] R₁₆ is selected from the group consisting of hydrido, acyl,aroyl, and trialkylsilyl;

[0093] R₁ is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R₁ has a higher Cahn-Ingold-Prelog stereochemical system rankingthan both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qpis Formula (III-P);

[0094] R₂ is hydrido;

[0095] R₂ can be selected from the group consisting of aryl, aralkyl,alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl,heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(Ap)Qp;

[0096] R₃ is selected from the group consisting of hydrido, hydroxy,cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl,heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl,carboxamide, and carboxamidoalkyl with the provisos that(CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical systemranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical systemranking than R₂;

[0097] Y is selected from the group consisting of covalent single bondand (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

[0098] R₁₄ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

[0099] Z is selected from the group consisting of covalent single bond,(C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 1;

[0100] W is oxy;

[0101] R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl,haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

[0102] R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido, halo, haloalkyl, and alkyl;

[0103] R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio,heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro,lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio,arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl,arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio,alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo,haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy,heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboxamido, carboxamidoalkyl, and cyano;

[0104] R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ andR₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independentlyselected from the group consisting of alkylene, alkenylene,alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene withthe provisos that no more than one of the group consisting of spacerpairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈ can be used at thesame time and that no more than one of the group consisting of spacerpairs R₉ and R₁₀, R₁₀and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be usedat the same time.

[0105] In a more preferred embodiment of compounds of Formula I-C,

[0106] n is an integer selected from 1 through 2;

[0107] R₁ is selected from the group consisting of haloalkyl andhaloalkoxymethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

[0108] R₁₆ is hydrido;

[0109] R₂ is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(Ap)Qp;

[0110] R₃ is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, and haloalkoxyalkyl with the provisos that(CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical systemranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical systemranking than R₂;

[0111] Y is selected from the group consisting of a covalent single bondand alkylene;

[0112] Z is selected from the group consisting of a covalent single bondand alkylene;

[0113] R₁₄ is selected from the group consisting of hydrido, alkyl, andhaloalkyl;

[0114] R₁₅ is selected from the group consisting of hydrido, alkyl, andhaloalkyl;

[0115] R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido and halo;

[0116] R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from thegroup consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl,heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.

[0117] In an even more preferred embodiment of compounds of Formula I-C,

[0118] n is the integer 1;

[0119] R₁₆ is hydrido;

[0120] R₁ is haloalkyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

[0121] R₂ is hydrido;

[0122] R₂ can be selected from the group consisting of alkyl, haloalkyl,aryl, and haloalkoxy with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

[0123] R₃ is selected from the group consisting of hydrido, alkyl, andhaloalkyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂;

[0124] Y is alkylene;

[0125] Z is covalent single bond;

[0126] R₁₄ is hydrido;

[0127] R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido and halo;

[0128] R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from thegroup consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, and heteroaryloxyalkyl.

[0129] In an embodiment of compounds of Formula I-C,

[0130] n is an integer selected from 1 to 3;

[0131] R₁ is selected from the group consisting of trifluoromethyl,

[0132] 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl,chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl,pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropylwith the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula(II-P) and Qp is Formula (III-P);

[0133] R₁₆ is selected from the group consisting of acetyl, benzoyl,dimethyl tert-butylsilyl, hydrido, and trimethylsilyl;

[0134] R₂ is hydrido;

[0135] R₂ can be selected from the group consisting of methyl, ethyl,propyl, butyl, isopropyl, isobutyl, vinyl, phenyl,4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl,trifluoromethoxymethyl, fluoromethyl, difluoromethyl,2,2,3,3,3-pentafluoropropyl, and and pentafluorophenoxymethyl with theproviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than bothR₁ and (CHR₃)_(n)—N(Ap)Qp;

[0136] R₃ is selected from the group consisting of hydrido, hydroxy,cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl,methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl,fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl,2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, andpentafluorophenoxymethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has alower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and ahigher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

[0137] In a preferred embodiment of compounds of Formula I-C, compoundshave the Formula I-CP:

[0138] or a phamaceutically acceptable salt thereof, wherein;

[0139] R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

[0140] R₂ is hydrido;

[0141] R₂ can be selected from the group consisting of methyl, ethyl,propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,and 2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

[0142] R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, ethyl, vinyl, methoxymethyl,trifluoromethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the provisos that(CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical systemranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical systemranking than R₂.

[0143] In a even more preferred embodiment of compounds of Formula I-CP,

[0144] R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

[0145] R₂ is hydrido;

[0146] R₂ can be selected from the group consisting of methyl, ethyl,phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl,1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, and2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

[0147] R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, andchlorodifluoromethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has alower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and ahigher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

[0148] In a most preferred embodiment of compounds of Formula I-CP,

[0149] R₁ is selected from the group consisting of trifluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

[0150] R₂ is hydrido;

[0151] R₂ can be phenyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

[0152] R₃ is selected from the group consisting of hydrido, methyl,trifluoromethyl, and difluoromethyl with the provisos that(CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical systemranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical systemranking than R₂.

[0153] In another embodiment of compounds of Formulas I-H or I-C, thecompounds correspond to the Cyclo I-H Formulas:

[0154] wherein:

[0155] K₁ and K₂ are independently selected from the group consisting ofC and N;

[0156] n is an integer selected from 1 through 3;

[0157] R₁ is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R₁ has a higher Cahn-Ingold-Prelog stereochemical system rankingthan both R₂ and (CHR₃)_(n)—N(Apch)Qph wherein Apch is Formula (II-PCH)and Qph is Formula (III-PH);

[0158] R₂ is hydrido;

[0159] R₂ is selected from the group consisting of aryl, aralkyl, alkyl,alkenyl, alkoxyalkyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl,heteroaryl, heteroarylalkyl, dicyanoalkyl, and carboalkoxycyanoalkylwith the proviso that R₂ has a lower Cahn-Ingold-Prelog system rankingthan both R₁ and (CHR₃)_(n)—N(Apch)Qph;

[0160] R₃ is selected from the group consisting of hydrido, hydroxy,halo, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl,heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl with theprovisos that (CHR₃)_(n)—N(Apch)Qph has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂;

[0161] Y is selected from the group consisting of a covalent single bondand (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

[0162] R₁₄ is selected from the group consisting of hydrido, hydroxy,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0163] Z is selected from the group consisting of covalent single bond,(C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and(CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independentlyselected from 0 through 1;

[0164] W is selected from the group consisting of O, C(O), S, S(O), andS(O)₂;

[0165] R₁₅ is selected from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0166] R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido, halo, haloalkyl, and alkyl;

[0167] R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy,cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy,aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl,perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl,heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl;

[0168] R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ andR₁₂, and R₁₂ and R₁₃ can be independently selected to form spacer pairswherein a spacer pair is taken together to form a linear moiety havingfrom 3 through 6 contiguous atoms connecting the points of bonding ofsaid spacer pair members to form a ring selected from the groupconsisting of a cycloalkenyl ring having 5 through 8 contiguous members,a partially saturated heterocyclyl ring having 5 through 8 contiguousmembers, a heteroaryl ring having 5 through 6 contiguous members, and anaryl with the provisos that no more than one of the group consisting ofspacer pairs R₅ and R₆, R₆ and R₇, and R₇ and R₈, can be used at thesame time and that no more than one of the group consisting of spacerpairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be usedat the same time.

[0169] In an embodiment of compounds of Formula Cyclo I-H,

[0170] n is the integer 1;

[0171] R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂and (CHR₃)_(n)—N(Apch)Qph wherein Apch is Formula (II-PCH) and Qph isFormula (III-PH);

[0172] R₂ is hydrido;

[0173] R₂ is selected from the group consisting of phenyl,-trifluoromethylphenyl, vinyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, and 2,2,3,3,3-pentafluoropropylwith the proviso that R₂ has a lower Cahn-Ingold-Prelog system rankingthan both R₁ and (CHR₃)_(n)—N(Apch)Qph;

[0174] R₃ is selected from the group consisting of hydrido, methyl,ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl,trifluoromethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the provisos that(CHR₃)_(n)—N(Apch)Qph has a lower Cahn-Ingold-Prelog stereochemicalsystem ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than R₂.

[0175] In another embodiment of compounds of Formula Cyclo I-H,

[0176] n is the integer 1;

[0177] R₁ is selected from the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl;

[0178] R₂ is hydrido;

[0179] R₃ is selected from the group consisting of hydrido, methyl,ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl,trifluoromethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the provisos that(CHR₃)_(n)—N(Apch)Qph has a lower Cahn-Ingold-Prelog stereochemicalsystem ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than R₂.

[0180] In a preferred embodiment of compounds of Formulas I-H, I-C,I-CP, and Cyclo I-H,

[0181] Y is selected from the group consisting of methylene, ethylene,and ethylidene;

[0182] Z is covalent single bond;

[0183] R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido and fluoro with the proviso that there is no R₄,R₈, R₉, or R₁₃ when the embodiment is a compound of Formula Cyclo I-H;

[0184] R₅ and R₁₀ are independently selected from the group consistingof 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy,4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy,4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy,chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-fluorobenzyl, 3-chloro-4-fluorophenyl,3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy,4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-ethylphenoxy,3-chloromethylphenoxy, 3-chloro-fluorophenoxy, 4-chloro-3-fluorophenoxy,4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy,4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy,cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl,cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy,2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl,3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy,2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy,2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl,3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy,2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy,2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl,1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy,3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro,4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl,4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy,3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy,2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy,tert-butoxy, 3-ter -butylphenoxy,4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio;

[0185] R₆ and R₁₁ are independently selected from the group consistingof chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy,trifluoromethyl, and trifluoromethoxy;

[0186] R₇ and R₁₂ are independently selected from the group consistingof hydrido, fluoro, and trifluoromethyl.

[0187] In an even more preferred embodiment of compounds of FormulasI-H, I-C, I-CP, and Cyclo I-H,

[0188] Y is methylene;

[0189] Z is covalent single bond;

[0190] R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido and fluoro with the proviso that there is no R₄,R₈, R₉, or R₁₃ when the embodiment is a compound of Formula Cyclo I-H;

[0191] R₅ and R₁₀ are independently selected from the group consistingof benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy,2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,2-chlorofluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy,3-chloroethylphenoxy, 3-chloro-4-methylphenoxy, 3-chlorofluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy,2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl,3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy,2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy,3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy,2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy,3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl,3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl,3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl,2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy,3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy,3-methylphenoxy, 3-methyl-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy,thiophen-3-yl,tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy,1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy,2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl,3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, andtrifluoromethylthio;

[0192] R₆ and R₁₁ are independently selected from the group consistingof chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy,and trifluoromethyl;

[0193] R₇ and R₁₂ are independently selected from the group consistingof hydrido, fluoro, and trifluoromethyl.

[0194] In a most preferred embodiment of compounds of Formulas I-H, I-C,I-CP, and Cyclo I-H,

[0195] Y is methylene;

[0196] Z is covalent single bond;

[0197] R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido and fluoro with the proviso that there is no R₄,R₈, R₉, or R₁₃ when the embodiment is a compound of Formula Cyclo I-H;

[0198] R₅ is selected from the group consisting of5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy,3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy,4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy,3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy,3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy,3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy;

[0199] R₁₀ is selected from the group consisting of cyclopentyl,1,1,2,2-tetrafluoroethoxy, 2-furyl,1,1-bis-trifluoromethyl-1-hydroxymethyl, isobutyl, isopropoxy,pentafluoroethyl, trifluoromethoxy, trifluoromethyl, andtrifluoromethylthio;

[0200] R₆ and R₁₁ are independently selected from the group consistingof fluoro and hydrido;

[0201] R₇ and R₁₂ are independently selected from the group consistingof hydrido and fluoro.

Definitions

[0202] The use of generic terms in the description of the compounds areherein defined for clarity.

[0203] Standard single letter elemental symbols are used to representspecific types of atoms unless otherwise defined. The symbol “C”represents a carbon atom. The symbol “O” represents an oxygen atom. Thesymbol “N” represents a nitrogen atom. The symbol “P” represents aphosphorus atom. The symbol “S” represents a sulfur atom. The symbol “H”represents a hydrogen atom. Double letter elemental symbols are used asdefined for the elements of the periodical table (i.e., Cl representschlorine, Se represents selenium, etc.).

[0204] As utilized herein, the term “alkyl”, either alone or withinother terms such as “haloalkyl” and “alkylthio”, means an acyclic alkylradical containing from 1 to about 10, preferably from 1 to about 8carbon atoms and more preferably 1 to about 6 carbon atoms. Said alkylradicals may be optionally substituted with groups as defined below.Examples of such radicals include methyl, ethyl, chloroethyl,hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl,isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl,octyl and the like.

[0205] The term “alkenyl” refers to an unsaturated, acyclic hydrocarbonradical in so much as it contains at least one double bond. Such alkenylradicals contain from about 2 to about 10 carbon atoms, preferably fromabout 2 to about 8 carbon atoms and more preferably 2 to about 6 carbonatoms. Said alkenyl radicals may be optionally substituted with groupsas defined below. Examples of suitable alkenyl radicals includepropenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl,2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl,3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

[0206] The term “alkynyl” refers to an unsaturated, acyclic hydrocarbonradical in so much as it contains one or more triple bonds, suchradicals containing about 2 to about 10 carbon atoms, preferably havingfrom about 2 to about 8 carbon atoms and more preferably having 2 toabout 6 carbon atoms. Said alkynyl radicals may be optionallysubstituted with groups as defined below. Examples of suitable alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl,3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl,3,3-dimethylbutyn-1-yl radicals and the like.

[0207] The term “hydrido” denotes a single hydrogen atom (H). Thishydrido radical may be attached, for example, to an oxygen atom to forma “hydroxyl” radical, one hydrido radical may be attached to a carbonatom to form a “methine” radical (═CH—), or two hydrido radicals may beattached to a carbon atom to form a “methylene” (—CH₂—) radical.

[0208] The term “carbon” radical denotes a carbon atom without anycovalent bonds and capable of forming four covalent bonds.

[0209] The term “cyano” radical denotes a carbon radical having three offour covalent bonds shared by a nitrogen atom.

[0210] The term “hydroxyalkyl” embraces radicals wherein any one or moreof the alkyl carbon atoms is substituted with a hydroxyl as definedabove. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl andpolyhydroxyalkyl radicals.

[0211] The term “alkanoyl” embraces radicals wherein one or more of theterminal alkyl carbon atoms are substituted with one or more carbonylradicals as defined below. Specifically embraced are monocarbonylalkyland dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicalsinclude formyl, acetyl, and pentanoyl. Examples of dicarbonylalkylradicals include oxalyl, malonyl, and succinyl.

[0212] The term “alkylene” radical denotes linear or branched radicalshaving from 1 to about 10 carbon atoms and having attachment points fortwo or more covalent bonds. Examples of such radicals are methylene,ethylene, ethylidene, methylethylene, and isopropylidene.

[0213] The term “alkenylene” radical denotes linear or branched radicalshaving from 2 to about 10 carbon atoms, at least one double bond, andhaving attachment points for two or more covalent bonds. Examples ofsuch radicals are 1,1-vinylidene (CH₂═C), 1,2-vinylidene (—CH═CH—), and1,4-butadienyl (—CH═CH—CH═CH—).

[0214] The term “halo” means halogens such as fluorine, chlorine,bromine or iodine atoms.

[0215] The term “haloalkyl” embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either abromo, chloro or a fluoro atom within the radical. Dihalo radicals mayhave two or more of the same halo atoms or a combination of differenthalo radicals and polyhaloalkyl radicals may have more than two of thesame halo atoms or a combination of different halo radicals. Morepreferred haloalkyl radicals are “lower haloalkyl” radicals having oneto about six carbon atoms. Examples of such haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

[0216] The term “hydroxyhaloalkyl” embraces radicals wherein any one ormore of the haloalkyl carbon atoms is substituted with hydroxy asdefined above. Examples of “hydroxyhaloalkyl” radicals includehexafluorohydoxypropyl.

[0217] The term “haloalkylene radical” denotes alkylene radicals whereinany one or more of the alkylene carbon atoms is substituted with halo asdefined above. Dihalo alkylene radicals may have two or more of the samehalo atoms or a combination of different halo radicals andpolyhaloalkylene radicals may have more than two of the same halo atomsor a combination of different halo radicals. More preferred haloalkyleneradicals are “lower haloalkylene” radicals having one to about sixcarbon atoms. Examples of “haloalkylene” radicals includedifluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkylsubstituted monofluoromethylene, and aryl substitutedtrifluoromethylene.

[0218] The term “haloalkenyl” denotes linear or branched radicals havingfrom 1 to about 10 carbon atoms and having one or more double bondswherein any one or more of the alkenyl carbon atoms is substituted withhalo as defined above. Dihaloalkenyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals andpolyhaloalkenyl radicals may have more than two of the same halo atomsor a combination of different halo radicals.

[0219] The terms “alkoxy” and “alkoxyalkyl” embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy radical. The term “alkoxyalkyl” alsoembraces alkyl radicals having one or more alkoxy radicals attached tothe alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylradicals. More preferred alkoxy radicals are “lower alkoxy” radicalshaving one to six carbon atoms. Examples of such radicals includemethoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The“alkoxy” radicals may be further substituted with one or more haloatoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” and“haloalkoxyalkyl” radicals. Examples of such haloalkoxy radicals includefluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, andfluoropropoxy. Examples of such haloalkoxyalkyl radicals includefluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl,difluoromethoxyethyl, and trifluoroethoxymethyl.

[0220] The terms “alkenyloxy” and “alkenyloxyalkyl” embrace linear orbranched oxy-containing radicals each having alkenyl portions of two toabout ten carbon atoms, such as ethenyloxy or propenyloxy radical. Theterm “alkenyloxyalkyl” also embraces alkenyl radicals having one or morealkenyloxy radicals attached to the alkyl radical, that is, to formmonoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferredalkenyloxy radicals are “lower alkenyloxy” radicals having two to sixcarbon atoms. Examples of such radicals include ethenyloxy, propenyloxy,butenyloxy, and isopropenyloxy alkyls. The “alkenyloxy” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkenyloxy” radicals. Examples of suchradicals include trifluoroethenyloxy, fluoroethenyloxy,difluoroethenyhloxy, and fluoropropenyloxy.

[0221] The term “haloalkoxyalkyl” also embraces alkyl radicals havingone or more haloalkoxy radicals attached to the alkyl radical, that is,to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term“haloalkenyloxy” also embraces oxygen radicals having one or morehaloalkenyloxy radicals attached to the oxygen radical, that is, to formmonohaloalkenyloxy and dihaloalkenyloxy radicals. The term“haloalkenyloxyalkyl” also embraces alkyl radicals having one or morehaloalkenyloxy radicals attached to the alkyl radical, that is, to formmonohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.

[0222] The term “alkylenedioxy” radicals denotes alkylene radicalshaving at least two oxygens bonded to a single alkylene group. Examplesof “alkylenedioxy” radicals include methylenedioxy, ethylenedioxy,alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. Theterm “haloalkylenedioxy” radicals denotes haloalkylene radicals havingat least two oxy groups bonded to a single haloalkyl group. Examples of“haloalkylenedioxy” radicals include difluoromethylenedioxy,tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstitutedmonofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.

[0223] The term “aryl”, alone or in combination, means a carbocyclicaromatic system containing one, two or three rings wherein such ringsmay be attached together in a pendant manner or may be fused. The term“fused” means that a second ring is present (ie, attached or formed) byhaving two adjacent atoms in common (ie, shared) with the first ring.The term “fused” is equivalent to the term “condensed”. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

[0224] The term “perhaloaryl” embraces aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the arylradical is substituted with 3 or more halo radicals as defined below.

[0225] The term “heterocyclyl” embraces saturated, partially saturatedand unsaturated heteroatom-containing ring-shaped radicals having from 5through 15 ring members selected from carbon, nitrogen, sulfur andoxygen, wherein at least one ring atom is a heteroatom. Heterocyclylradicals may contain one, two or three rings wherein such rings may beattached in a pendant manner or may be fused. Examples of saturatedheterocyclic radicals include saturated 3 to 6-membered heteromonocylicgroup containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partiallysaturated heterocyclyl radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclicradicals, also termed “heteroaryl” radicals, include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrirnidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.;unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl,etc.] and the like. The term also embraces radicals where heterocyclicradicals are fused with aryl radicals. Examples of such fused bicyclicradicals include benzofuran, benzothiophene, and the like. Said“heterocyclyl” group may have 1 to 3 substituents as defined below.Preferred heterocyclic radicals include five to twelve membered fused orunfused radicals. Non-limiting examples of heterocyclic radicals includepyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl,pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl,furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl,1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and thelike.

[0226] The term “sulfonyl”, whether used alone or linked to other termssuch as alkylsulfonyl, denotes respectively divalent radicals —SO₂—.“Alkylsulfonyl”, embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. “Alkylsulfonylalkyl”, embracesalkylsulfonyl radicals attached to an alkyl radical, where alkyl isdefined as above. “Haloalkylsulfonyl”, embraces haloalkyl radicalsattached to a sulfonyl radical, where haloalkyl is defined as above.“Haloalkylsulfonylalkyl”, embraces haloalkylsulfonyl radicals attachedto an alkyl radical, where alkyl is defined as above. The term“aminosulfonyl” denotes an amino radical attached to a sulfonyl radical.

[0227] The term “sulfinyl”, whether used alone or linked to other termssuch as alkylsulfinyl, denotes respectively divalent radicals —S(O)—.“Alkylsulfinyl”, embraces alkyl radicals attached to a sulfinyl radical,where alkyl is defined as above. “Alkylsulfinylalkyl”, embracesalkylsulfinyl radicals attached to an alkyl radical, where alkyl isdefined as above. “Haloalkylsulfinyl”, embraces haloalkyl radicalsattached to a sulfinyl radical, where haloalkyl is defined as above.“Haloalkylsulfinylalkyl”, embraces haloalkylsulfinyl radicals attachedto an alkyl radical, where alkyl is defined as above.

[0228] The term “aralkyl” embraces aryl-substituted alkyl radicals.Preferable aralkyl radicals are “lower aralkyl” radicals having arylradicals attached to alkyl radicals having one to six carbon atoms.Examples of such radicals include benzyl, diphenylmethyl,triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl andphenylmethyl are interchangeable.

[0229] The term “heteroaralkyl” embraces heteroaryl-substituted alkylradicals wherein the heteroaralkyl radical may be additionallysubstituted with three or more substituents as defined above for aralkylradicals. The term “perhaloaralkyl” embraces aryl-substituted alkylradicals wherein the aralkyl radical is substituted with three or morehalo radicals as defined above.

[0230] The term “aralkylsulfinyl”, embraces aralkyl radicals attached toa sulfinyl radical, where aralkyl is defined as above.“Aralkylsulfinylalkyl”, embraces aralkylsulfinyl radicals attached to analkyl radical, where alkyl is defined as above.

[0231] The term “aralkylsulfonyl”, embraces aralkyl radicals attached toa sulfonyl radical, where aralkyl is defined as above.“Aralkylsulfonylalkyl”, embraces aralkylsulfonyl radicals attached to analkyl radical, where alkyl is defined as above.

[0232] The term “cycloalkyl” embraces radicals having three to tencarbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl”radicals having three to seven carbon atoms. Examples include radicalssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. The term “cycloalkylalkyl” embraces cycloalkyl-substitutedalkyl radicals. Preferable cycloalkylalkyl radicals are “lowercycloalkylalkyl” radicals having cycloalkyl radicals attached to alkylradicals having one to six carbon atoms. Examples of such radicalsinclude cyclohexylhexyl. The term “cycloalkenyl” embraces radicalshaving three to ten carbon atoms and one or more carbon-carbon doublebonds. Preferred cycloalkenyl radicals are “lower cycloalkenyl” radicalshaving three to seven carbon atoms. Examples include radicals such ascyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term“halocycloalkyl” embraces radicals wherein any one or more of thecycloalkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohalocycloalkyl, dihalocycloalkyl andpolyhalocycloalkyl radicals. A monohalocycloalkyl radical, for oneexample, may have either a bromo, chloro or a fluoro atom within theradical. Dihalo radicals may have two or more of the same halo atoms ora combination of different halo radicals and polyhalocycloalkyl radicalsmay have more than two of the same halo atoms or a combination ofdifferent halo radicals. More preferred halocycloalkyl radicals are“lower halocycloalkyl” radicals having three to about eight carbonatoms. Examples of such halocycloalkyl radicals includefluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl,tetrafluorocyclohexyl, and dichlorocyclopropyl. The term“halocycloalkenyl” embraces radicals wherein any one or more of thecycloalkenyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl andpolyhalocycloalkenyl radicals.

[0233] The term “cycloalkoxy” embraces cycloalkyl radicals attached toan oxy radical. Examples of such radicals includes cyclohexoxy andcyclopentoxy. The term “cycloalkoxyalkyl” also embraces alkyl radicalshaving one or more cycloalkoxy radicals attached to the alkyl radical,that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals.Examples of such radicals include cyclohexoxyethyl. The “cycloalkoxy”radicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide “halocycloalkoxy” and“halocycloalkoxyalkyl” radicals.

[0234] The term “cycloalkylalkoxy” embraces cycloalkyl radicals attachedto an alkoxy radical. Examples of such radicals includescyclohexylmethoxy and cyclopentylmethoxy.

[0235] The term “cycloalkenyloxy” embraces cycloalkenyl radicalsattached to an oxy radical. Examples of such radicals includescyclohexenyloxy and cyclopentenyloxy. The term “cycloalkenyloxyalkyl”also embraces alkyl radicals having one or more cycloalkenyloxy radicalsattached to the alkyl radical, that is, to form monocycloalkenyloxyalkyland dicycloalkenyloxyalkyl radicals. Examples of such radicals includecyclohexenyloxyethyl. The “cycloalkenyloxy” radicals may be furthersubstituted with one or more halo atoms, such as fluoro, chloro orbromo, to provide “halocycloalkenyloxy” and “halocycloalkenyloxyalkyl”radicals.

[0236] The term “cycloalkylenedioxy” radicals denotes cycloalkyleneradicals having at least two oxygens bonded to a single cycloalkylenegroup. Examples of “alkylenedioxy” radicals include1,2-dioxycyclohexylene.

[0237] The term “cycloalkylsulfinyl”, embraces cycloalkyl radicalsattached to a sulfinyl radical, where cycloalkyl is defined as above.“Cycloalkylsulfinylalkyl”, embraces cycloalkylsulfinyl radicals attachedto an alkyl radical, where alkyl is defined as above. The term“Cycloalkylsulfonyl”, embraces cycloalkyl radicals attached to asulfonyl radical, where cycloalkyl is defined as above.“Cycloalkylsulfonylalkyl”, embraces cycloalkylsulfonyl radicals attachedto an alkyl radical, where alkyl is defined as above.

[0238] The term “cycloalkylalkanoyl” embraces radicals wherein one ormore of the cycloalkyl carbon atoms are substituted with one or morecarbonyl radicals as defined below. Specifically embraced aremonocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples ofmonocarbonylcycloalkyl radicals include cyclohexylcarbonyl,cyclohexylacetyl, and cyclopentylcarbonyl. Examples ofdicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane.

[0239] The term “alkylthio” embraces radicals containing a linear orbranched alkyl radical, of one to ten carbon atoms, attached to adivalent sulfur atom. More preferred alkylthio radicals are “loweralkylthio” radicals having one to six carbon atoms. An example of “loweralkylthio” is methylthio (CH₃—S—). The “alkylthio” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkylthio” radicals. Examples of such radicalsinclude fluoromethylthio, chloromethylthio, trifluoromethylthio,difluoromethylthio, trifluoroethylthio, fluoroethylthio,tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.

[0240] The term “alkyl aryl amino” embraces radicals containing a linearor branched alkyl radical, of one to ten carbon atoms, and one arylradical both attached to an amino radical. Examples includeN-methyl4-methoxyaniline, N-ethyl-4-methoxyaniline, andN-methyl-4-trifluoromethoxyaniline.

[0241] The terms alkylamino denotes “monoalkylamino” and “dialkylamino”containing one or two alkyl radicals, respectively, attached to an aminoradical.

[0242] The terms arylamino denotes “monoarylamino” and “diarylamino”containing one or two aryl radicals, respectively, attached to an aminoradical. Examples of such radicals include N-phenylamino andN-naphthylamino.

[0243] The term “aralkylamino”, embraces aralkyl radicals attached to anamino radical, where aralkyl is defined as above. The term aralkylaminodenotes “monoaralkylamino” and “diaralkylamino” containing one or twoaralkyl radicals, respectively, attached to an amino radical. The termaralkylamino further denotes “monoaralkyl monoalkylamino” containing onearalkyl radical and one alkyl radical attached to an amino radical.

[0244] The term “arylsulfinyl” embraces radicals containing an arylradical, as defined above, attached to a divalent S(═O) atom. The term“arylsulfinylalkyl” denotes arylsulfinyl radicals attached to a linearor branched alkyl radical, of one to ten carbon atoms.

[0245] The term “arylsulfonyl”, embraces aryl radicals attached to asulfonyl radical, where aryl is defined as above. “arylsulfonylalkyl”,embraces arylsulfonyl radicals attached to an alkyl radical, where alkylis defined as above. The term “heteroarylsulfinyl” embraces radicalscontaining an heteroaryl radical, as defined above, attached to adivalent S(═O) atom. The term “heteroarylsulfinylalkyl” denotesheteroarylsulfinyl radicals attached to a linear or branched alkylradical, of one to ten carbon atoms. The term “Heteroarylsulfonyl”,embraces heteroaryl radicals attached to a sulfonyl radical, whereheteroaryl is defined as above. “Heteroarylsulfonylalkyl”, embracesheteroarylsulfonyl radicals attached to an alkyl radical, where alkyl isdefined as above.

[0246] The term “aryloxy” embraces aryl radicals, as defined above,attached to an oxygen atom. Examples of such radicals include phenoxy,4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloroethylphenoxy,3,4-dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy,3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy,5-bromo-2-fluorophenoxy, -fluorophenoxy, 4-bromo-3-fluorophenoxy,4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy,3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy,4-tert-butylphenoxy, 3-pentafluoroethylphenoxy, and3-(1,1,2,2-tetrafluoroethoxy)phenoxy. The term “aroyl” embraces arylradicals, as defined above, attached to an carbonyl radical as definedabove. Examples of such radicals include benzoyl and toluoyl.

[0247] The term “aralkanoyl” embraces aralkyl radicals, as definedherein, attached to an carbonyl radical as defined above. Examples ofsuch radicals include, for example, phenylacetyl.

[0248] The term “aralkoxy” embraces oxy-containing aralkyl radicalsattached through an oxygen atom to other radicals. More preferredaralkoxy radicals are “lower aralkoxy” radicals having phenyl radicalsattached to lower alkoxy radical as described above. Examples of suchradicals include benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3-bromobenzyloxy,4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and2-phenylethoxy.

[0249] The term “aryloxyalkyl” embraces aryloxy radicals, as definedabove, attached to an alkyl group. Examples of such radicals includephenoxymethyl.

[0250] The term “haloaryloxyalkyl” embraces aryloxyalkyl radicals, asdefined above, wherein one to five halo radicals are attached to anaryloxy group.

[0251] The term “heteroaroyl” embraces heteroaryl radicals, as definedabove, attached to an carbonyl radical as defined above. Examples ofsuch radicals include furoyl and nicotinyl.

[0252] The term “heteroaralkanoyl” embraces heteroaralkyl radicals, asdefined herein, attached to an carbonyl radical as defined above.Examples of such radicals include, for example, pyridylacetyl andfurylbutyryl.

[0253] The term “heteroaralkoxy” embraces oxy-containing heteroaralkylradicals attached through an oxygen atom to other radicals. Morepreferred heteroaralkoxy radicals are “lower heteroaralkoxy” radicalshaving heteroaryl radicals attached to lower alkoxy radical as describedabove.

[0254] The term “haloheteroaryloxyalkyl” embraces heteroaryloxyalkylradicals, as defined above, wherein one to four halo radicals areattached to an heteroaryloxy group.

[0255] The term “heteroarylamino” embraces heterocyclyl radicals, asdefined above, attached to an amino group. Examples of such radicalsinclude pyridylamino.

[0256] The term “heteroarylaminoalkyl” embraces heteroarylaminoradicals, as defined above, attached to an alkyl group. Examples of suchradicals include pyridylmethylamino.

[0257] The term “heteroaryloxy” embraces heterocyclyl radicals, asdefined above, attached to an oxy group. Examples of such radicalsinclude 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and4-pyridyloxy.

[0258] The term “heteroaryloxyalkyl” embraces heteroaryloxy radicals, asdefined above, attached to an alkyl group. Examples of such radicalsinclude 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.

[0259] The term “arylthio” embraces aryl radicals, as defined above,attached to an sulfur atom. Examples of such radicals includephenylthio.

[0260] The term “arylthioalkyl” embraces arylthio radicals, as definedabove, attached to an alkyl group. Examples of such radicals includephenylthiomethyl.

[0261] The term “alkylthioalkyl” embraces alkylthio radicals, as definedabove, attached to an alkyl group. Examples of such radicals includemethylthiomethyl. The term “alkoxyalkyl” embraces alkoxy radicals, asdefined above, attached to an alkyl group. Examples of such radicalsinclude methoxymethyl.

[0262] The term “carbonyl” denotes a carbon radical having two of thefour covalent bonds shared with an oxygen atom. The term “carboxy”embraces a hydroxyl radical, as defined above, attached to one of twounshared bonds in a carbonyl group. The term “carboxamide” embracesamino, monoalkylamino, dialkylamino, monocycloalkylamino,alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one oftwo unshared bonds in a carbonyl group. The term “carboxamidoalkyl”embraces carboxamide radicals, as defined above, attached to an alkylgroup. The term “carboxyalkyl” embraces a carboxy radical, as definedabove, attached to an alkyl group. The term “carboalkoxy” embracesalkoxy radicals, as defined above, attached to one of two unshared bondsin a carbonyl group. The term “carboaralkoxy” embraces aralkoxyradicals, as defined above, attached to one of two unshared bonds in acarbonyl group. The term “monocarboalkoxyalkyl” embraces one carboalkoxyradical, as defined above, attached to an alkyl group. The term“dicarboalkoxyalkyl” embraces two carboalkoxy radicals, as definedabove, attached to an alkylene group. The term “monocyanoalkyl” embracesone cyano radical, as defined above, attached to an alkyl group. Theterm “dicyanoalkylene” embraces two cyano radicals, as defined above,attached to an alkyl group. The term “carboalkoxycyanoalkyl” embracesone cyano radical, as defined above, attached to an carboalkoxyalkylgroup.

[0263] The term “acyl”, alone or in combination, means a carbonyl orthionocarbonyl group bonded to a radical selected from, for example,hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl,haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy,arylthio, and alkylthioalkyl. Examples of “acyl” are formyl, acetyl,benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.The term “haloalkanoyl” embraces one or more halo radicals, as definedherein, attached to an alkanoyl radical as defined above. Examples ofsuch radicals include, for example, chloroacetyl, trifluoroacetyl,bromopropanoyl, and heptafluorobutanoyl. The term “diacyl”, alone or incombination, means having two or more carbonyl or thionocarbonyl groupsbonded to a radical selected from, for example, alkylene, alkenylene,alkynylene, haloalkylene, alkoxyalkylene, aryl, heterocyclyl,heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl.Examples of “diacyl” are phthaloyl, malonyl, succinyl, adipoyl, and thelike.

[0264] The term “benzylidenyl” radical denotes substituted andunsubstituted benzyl groups having attachment points for two covalentbonds. One attachment point is through the methylene of the benzyl groupwith the other attachment point through an ortho carbon of the phenylring. The methylene group is designated for attached to the lowestnumbered position. Examples include the base compound benzylidene ofstructure:

[0265] The term “phenoxylidenyl” radical denotes substituted andunsubstituted phenoxy groups having attachment points for two covalentbonds. One attachment point is through the oxy of the phenoxy group withthe other attachment point through an ortho carbon of the phenyl ring.The oxy group is designated for attached to the lowest numberedposition. Examples include the base compound phenoxylidene of structure:

[0266] The term “phosphono” embraces a pentavalent phosphorus attachedwith two covalent bonds to an oxygen radical. The term“dialkoxyphosphono” denotes two alkoxy radicals, as defined above,attached to a phosphono radical with two covalent bonds. The term“diaralkoxyphosphono” denotes two aralkoxy radicals, as defined above,attached to a phosphono radical with two covalent bonds. The term“dialkoxyphosphonoalkyl” denotes dialkoxyphosphono radicals, as definedabove, attached to an alkyl radical. The term “diaralkoxyphosphonoalkyl”denotes diaralkoxyphosphono radicals, as defined above, attached to analkyl radical.

[0267] Said “alkyl”, “alkenyl”, “alkynyl”, “alkanoyl”, “alkylene”,“alkenylene”, “benzylidenyl”, “phenoxylidenyl”, “hydroxyalkyl”,“haloalkyl”, “haloalkylene”, “haloalkenyl”, “alkoxy”, “alkenyloxy”,“alkenyloxyalkyl”, “alkoxyalkyl”, “aryl”, “perhaloaryl”, “haloalkoxy”,“haloalkoxyalkyl”, “haloalkenyloxy”, “haloalkenyloxyalkyl”,“alkylenedioxy”, “haloalkylenedioxy”, “heterocyclyl”, “heteroaryl”,“hydroxyhaloalkyl”, “alkylsulfonyl”, “haloalkylsulfonyl”,“alkylsulfonylalkyl”, “haloalkylsulfonylalkyl”, “alkylsulfinyl”,“alkylsulfinylalkyl”, “haloalkylsulfinylalkyl”, “aralkyl”,“heteroaralkyl”, “perhaloaralkyl”, “aralkylsulfonyl”,“aralkylsulfonylalkyl”, “aralkylsulfinyl”, “aralkylsulfinylalkyl”,“cycloalkyl”, “cycloalkylalkanoyl”, “cycloalkylalkyl”, “cycloalkenyl”,“halocycloalkyl”, “halocycloalkenyl”, “cycloalkylsulfinyl”,“cycloalkylsulfinylalkyl”, “cycloalkylsulfonyl”,“cycloalkylsulfonylalkyl”, “cycloalkoxy”, “cycloalkoxyalkyl”,“cycloalkylalkoxy”, “cycloalkenyloxy”, “cycloalkenyloxyalkyl”,“cycloalkylenedioxy”, “halocycloalkoxy”, “halocycloalkoxyalkyl”,“halocycloalkenyloxy”, “halocycloalkenyloxyalkyl”, “alkylthio”,“haloalkylthio”, “alkylsulfinyl”, “amino”, “oxy”, “thio”, “alkylamino”,“arylamino”, “aralkylamino”, “arylsulfinyl”, “arylsulfinylalkyl”,“arylsulfonyl”, “arylsulfonylalkyl”, “heteroarylsulfinyl”,“heteroarylsulfinylalkyl”, “heteroarylsulfonyl”,“heteroarylsulfonylalkyl”, “heteroarylamino”, “heteroarylaminoalkyl”,“heteroaryloxy”, “heteroaryloxylalkyl”, “aryloxy”, “aroyl”,“aralkanoyl”, “aralkoxy”, “aryloxyalkyl”, “haloaryloxyalkyl”,“heteroaroyl”, “heteroaralkanoyl”, “heteroaralkoxy”,“heteroaralkoxyalkyl”, “arylthio”, “arylthioalkyl”, “alkoxyalkyl”,“acyl” and “diacyl” groups defined above may optionally have 1 to 5non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy,alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy,cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partiallysaturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl,arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido,carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl,diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

[0268] The term “spacer” can include a covalent bond and a linear moietyhaving a backbone of 1 to 7 continous atoms. The spacer may have 1 to 7atoms of a univalent or multi-valent chain. Univalent chains may beconstituted by a radical selected from ═C(H)—, ═C(R₁₇)—, —O—, —S—,—S(O)—, —S(O)₂—, —NH—, —N(R₁₇)—, —N═, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—,═C(OR₁₇)—, and —C(O)— wherein R₁₇ is selected from alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl.Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6atoms with a side chain. The chain may be constituted of one or moreradicals selected from: lower alkylene, lower alkenyl, —O—, —O—CH₂—,—S—CH₂—, —CH₂CH₂—, ethenyl, —CH═CH(OH)—, —OCH₂O—, —O(CH₂)₂O—, —NHCH₂—,—OCH(R₁₇)O—, —OCF₂O—, —O(CF₂)₂O—, —S—, —S(O)—, —S(O)₂—, —N(H)—, —N(H)O—,—N(R₁₇)O—, —N(R₁₇)—, —C(O)—, —C(O)NH—, —C(O)NR₁₇—, —N═, —OCH₂—, —SCH₂—,S(O)CH₂—, —CH₂C(O)—, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—, ═C(OR₁₇)—,S(O)₂CH₂—, and —NR₁₇CH₂— and many other radicals defined above orgenerally known or ascertained by one of skill-in-the art. Side chainsmay include substituents such as 1 to 5 non-hydrido substituents such asperhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy,heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy,alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partiallysaturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl,arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl,cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono,and diaralkoxyphosphonoalkyl.

[0269] Chiral compounds of the present invention have a hydroxyl groupsubstitutent on a chiral carbon of the alkanol and propanol compounds ofthe present invention specifically in the R-stereoisomeric configurationbased on the Cahn-Ingold-Prelog convention for stereoisomeric carbonatoms. The R-stereoisomeric configuration compounds of the presentinvention may optionally have one or more additional chiral carbonspresent in each compound. The R-stereoisomeric configuration compoundsof the present invention can exist in tautomeric, geometric, and otherstereoisomeric forms. The present invention having a hydroxyl groupsubstitutent on a chiral carbon of the alkanol and propanol compounds inthe R-stereoisomeric configuration contemplates all such forms of saidinvented compounds, including cis- and trans-geometric isomers, E- andZ-geometric isomers, diastereomers, and other mixtures thereof, asfalling within the scope of the invention. Pharmaceutically acceptablesales of such tautomeric, geometric or stereoisomeric forms are alsoincluded within the invention. The standard definitions for theCahn-Ingold-Prelog convention and stereochemical system can be found inPure Applied Chemistry, 1976, Vol. 45, pages 15-30 and Cahn et al.,Angewandte Chemie International Edition English, 1966, Vol. 5, pages385-415.

[0270] The terms “cis” and “trans” denote a form of geometric isomerismin which two carbon atoms connected by a double bond will each have ahydrogen atom on the same side of the double bond (“cis”) or on oppositesides of the double bond (“trans”).

[0271] Some of the compounds described contain alkenyl groups, and aremeant to include both cis and trans or “E” and “Z” geometric forms.

[0272] Some of the compounds described contain one or more stereocentersin addition to said hydroxyl group substitutent on a chiral carbon ofthe alkanol and propanol compounds in the R-stereoisomeric configurationand are meant to include R, S, and mixtures of R and S forms for eachadditional stereocenter present.

[0273] Some of the compounds described herein may contain one or moreketonic or aldehydic carbonyl groups or combinations thereof alone or aspart of a heterocyclic ring system. Such carbonyl groups may exist inpart or principally in the “keto” form and in part or principally as oneor more “enol” forms of each aldehyde and ketone group present.Compounds of the present invention having aldehydic or ketonic carbonylgroups are meant to include both “keto” and “enol” tautomeric forms.

[0274] Some of the compounds described herein may contain one or moreamide carbonyl groups or combinations thereof alone or as part of aheterocyclic ring system. Such carbonyl groups may exist in part orprincipally in the “keto” form and in part or principally as one or more“enol” forms of each amide group present. Compounds of the presentinvention having amidic carbonyl groups are meant to include both “keto”and “enol” tautomeric forms. Said amide carbonyl groups may be both oxo(C═O) and thiono (C═S) in type.

[0275] Some of the compounds described herein may contain one or moreimine or enamine groups or combinations thereof. Such groups may existin part or principally in the “imine” form and in part or principally asone or more “enamine” forms of each group present. Compounds of thepresent invention having said imine or enamine groups are meant toinclude both “imine” and “enamine” tautomeric forms.

[0276] The following general synthetic sequences are useful in makingthe present invention. Abbreviations used in the schemes are as follows:“AA” represents amino acids, “BINAP” represents2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, “Boc” representstert-butyloxycarbonyl, “BOP” representsbenzotriazol-1-yl-oxy-tris-(dimethylamino), “bu” represents butyl, “dba”represents dibenzylideneacetone, “DCC” represents1,3-dicyclohexylcarbodiimide, “DIBAH” represents diisobutylaluminumhydride, “DIPEA” represents diisopropylethylamine, “DMF” representsdimethylformamide, “DMSO” represents dimethylsulfoxide, “Fmoc”represents 9-fluorenylmethoxycarbonyl, “LDA” represents lithiumdiisopropylamide, “PHTH” represents a phthaloyl group, “pnZ” represents4-nitrobenzyloxycarbonyl, “PTC” represents a phase transfer catalyst,“p-TsOIH” represents paratoluenesulfonic acid, “TBAF” representstetrabutylammonium fluoride, “TBTU” represents2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate,“TEA” represents triethylamine, “TFA” represents trifluoroacetic acid,“THF” represents tetrahydrofuran, “TMS” represents trimethylsilyl, and“Z” represents benzyloxycarbonyl.

[0277] The present invention comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of FormulasI-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP inassociation with at least one pharmaceutically-acceptable carrier,adjuvant or diluent.

[0278] The present invention also comprises a treatment and prophylaxisof coronary artery disease and other CETP-mediated disorders in asubject, comprising administering to the subject having such disorder atherapeutically-effective amount of a compound of Formula I-H:

[0279] or a pharmaceutically-acceptable salt thereof, wherein R₁, R₂,R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, X, Y, andZ are as defined above for the compounds of Formula I-H.

[0280] As a further embodiment, compounds of the present invention ofFormulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and CycloI-CP or a pharmaceutically-acceptable salt thereof as defined abovecomprise a treatment and prophylaxis of coronary artery disease andother CETP-mediated disorders in a subject, comprising administering tothe subject having such disorder a therapeutically-effective amount ofcompounds I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and CycloI-CP of the present invention or a pharmaceutically-acceptable saltthereof.

[0281] Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H,Cyclo I-C, and Cyclo I-CP are capable of inhibiting activity ofcholesteryl ester transfer protein (CETP), and thus could be used in themanufacture of a medicament, a method for the prophylactic ortherapeutic treatment of diseases mediated by CETP, such as peripheralvascular disease, hyperlipidaemia, hypercholesterolemia, and otherdiseases attributable to either high LDL and low HDL or a combination ofboth, or a procedure to study the mechanism of action of the cholesterylester transfer protein (CETP) to enable the design of better inhibitors.The compounds of Formula I-H would be also useful in prevention ofcerebral vascular accident (CVA) or stroke.

[0282] Also included in the family of compounds of Formula I-H, I-HP,I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I-H may be prepared frominorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic,cyclohexylaminosulfonic, algenic, galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaV-H include metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromN,N′-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procain. All of thesesalts may be prepared by conventional means from the correspondingcompound of Formula I-H by reacting, for example, the appropriate acidor base with the compound of Formula I-H.

[0283] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I-H inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The active compounds andcomposition may, for example, be administered orally, intravascularly,intraperitoneally, subcutaneously, intramuscularly or topically.

[0284] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

[0285] The amount of therapeutically active compounds which areadministered and the dosage regimen for treating a disease conditionwith the compounds and/or compositions of this invention depends on avariety of factors, including the age, weight, sex and medical conditionof the subject, the severity of the disease, the route and frequency ofadministration, and the particular compound employed, and thus may varywidely.

[0286] The pharmaceutical compositions may contain active ingredients inthe range of about 0.1 to 2000 mg, and preferably in the range of about0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, andpreferably between about 0.5 and about 20 mg/kg body weight, may beappropriate. The daily dose can be administered in one to four doses perday.

[0287] The compounds may be formulated in topical ointment or cream, oras a suppository, containing the active ingredients in a total amountof, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and mostpreferably 0.4 to 15% w/w. When formulated in an ointment, the activeingredients may be employed with either paraffinic or a water-miscibleointment base. Alternatively, the active ingredients may be formulatedin a cream with an oil-in-water cream base. If desired, the aqueousphase of the cream base may include, for example at least 30% w/w of apolyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol,sorbitol, glycerol, polyethylene glycol and mixtures thereof. Thetopical formulation may desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethylsulfoxide and related analogs. The compounds of thisinvention can also be administered by a transdermal device. Preferablytopical administration will be accomplished using a patch either of thereservoir and porous membrane type or of a solid matrix variety. Ineither case, the active agent is delivered continuously from thereservoir or microcapsules through a membrane into the active agentpermeable adhesive, which is in contact with the skin or mucosa of therecipient. If the active agent is absorbed through the skin, acontrolled and predetermined flow of the active agent is administered tothe recipient. In the case of microcapsules, the encapsulating agent mayalso function as the membrane.

[0288] The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

[0289] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties, since the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[0290] For therapeutic purposes, the active compounds of thiscombination invention are ordinarily combined with one or more adjuvantsappropriate to the indicated route of administration. If administeredper os, the compounds may be admixed with lactose, sucrose, starchpowder, cellulose esters of alkanoic acids, cellulose alkyl esters,talc, stearic acid, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

[0291] The present invention further comprises a process for thepreparation of (R)-chiral compounds of Formulas I-H, I-HP, I-C, I-CP,I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP by reacting suitablesecondary amines with (R)-chiral forms of alcohols, epoxides, and cyclicsulfate esters.

[0292] The present invention also comprises a process for thepreparation of (R)-chiral compounds of Formulas I-H, I-HP, I-C, I-CP,I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP by reacting a suitablesecondary amine with a substantially stoichiometric amount of a(R)-chiral epoxide in the presence of a transition metal-based salt.

[0293] The present invention also comprises a process for thepreparation of (R)-chiral precursor compounds useful in the preparationof compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, CycloI-C, and Cyclo I-CP by reacting a suitable primary amine with asubstantially stoichiometric amount of a (R)-chiral epoxide with orwithout the presence of an added transition metal-based compound.

[0294] All mentioned references are incorporated by reference as if herewritten.

[0295] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations.

General Synthetic Procedures

[0296] The compounds of the present invention can be synthesized, forexample, according to the following procedures of Schemes 1 through 58below, wherein the substituents are as defined for Formulas I-H, I-HP,I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP above exceptwhere further noted.

[0297] Synthetic Schemes 1 and 2 shows the preparation of compounds offormula XIII (“Generic Secondary Amines”) which are intermediates in thepreparation of the compounds of the present invention corresponding toFormula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral HalogenatedI-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) wherein Aand Q are independently aryl and heteroaryl. Schemes 1 and 2, takentogether, prepare 1-substitutedamino-2-alkanols of the present inventionby addition of a halogenated, oxygen containing precursor to a secondaryamine to introduce an oxy containing alkyl group wherein the two groupsmaking up the secondary amine both are made up of aromatic groups orboth groups contain aromatic rings wherein said aromatic rings maybe 0to 2 aryl rings and 0 to 2 heteroaryl rings.

[0298] The “Generic Imine” corresponding to Formula XII can be preparedthrough dehydration techniques generally known in the art and thepreferred technique depending on the nature of “Generic Amine-I” ofFormula X by reacting it with the “Generic Carbonyl Compound” of FormulaXI. For example, when Z is a covalent bond, methylene, methinesubstituted with another subsitutent, ethylene, or another subsituent asdefined in Formula I-H, the two reactants (X and XI) react by refluxingthem in an aprotic solvent, such as hexane, toluene, cyclohexane,benzene, and the like, using a Dean-Stark type trap to remove water.After about 2-8 hours or until the removal of water is complete, theaprotic solvent is removed in vacuo to yield the “Generic Imine” ofFormula XII. Alternately, when Z is an oxygen, the “Generic Imine” is anoxime derivative. Oxime type “Generic Imine” compounds are readilyprepared from the corresponding O-substituted hydroxylamine and theappropriate aldehyde or ketone type “Generic Carbonyl Compound”.Suitable procedures are described by Shriner, Fuson, and Curtin in TheSystematic Indentification of Organic Compounds, 5th Edition, John Wiley& Sons and by Fieser and Fieser in Reagents for Organic Synthesis,Volume 1, John Wiley & Sons, which are incorporated herein by reference.Alternately, when Z is a nitrogen, the “Generic Imine” is a hydrazonederivative. Hydrazone type “Generic Imine” compounds are readilyprepared from the corresponding hydrazine and the appropriate aldehydeor ketone type “Generic Carbonyl Compound”. Suitable procedures forforming the hydrazone imines are also described by Shriner, Fuson, andCurtin in The Systematic Indentification of Organic Compounds, 5thEdition, John Wiley & Sons, and by Fieser and Fieser in Reagents forOrganic Synthesis, Volume 1, John Wiley & Sons, which are incorporatedherein by reference.

[0299] Scheme 1 shows the preparation of “Generic Imine” compounds inwhich the amine functionality is bonded to Z; Z is bonded to A; and Y isbonded to Q. One of skill in the art will recognize that A and Q asdefined can be structurally interchanged to prepare “Generic Imine”compounds with similar, identical or different structures.

[0300] The “Generic Secondary Amines” of Formula XIII can be preparedfrom the corresponding “Generic Imine” of Formula XII in several ways.

[0301] For example, in one synthetic scheme (Reduction Method-1), whichis preferred when Z is a nitrogen, the “Generic Imine” hydrazone ofFormula XII is partially or completely dissolved in lower alkanols suchas ethanol or like solvent containing sufficient organic acid such asacetic acid or mineral acid such as HCl or sulfuric acid to neutralizethe hydrazone as described in WO Patent Application No.9738973, SwissPatent CH 441366 and U.S. Pat. Nos. 3,359,316 and 3,334,017, which areincorporated herein by reference. The resulting mixture is thenhydrogenated at 0-100° C., more preferrably 20-50° C., and mostpreferrably between 20-30° C. and pressures of 10-200 psi hydrogen ormore preferrably between 50-70 psi hydrogen in the presence of a noblemetal catalyst such as PtO₂. The mixture is cooled, and a base such assodium carbonate or sodium hydroxide added until the solution is neutralto just alkaline (pH 6-8).

[0302] Isolation of the desired product can be accomplished, forexample, by removing the ethanol, adding water, and extracting theaqueous-organic mixture twice with a solvent, such as diethyl ether ormethylene chloride, that is immiscible with water. The combined solventextract is washed with saturated brine, dried with a drying agent suchas anhydrous magnesium sulfate, and concentrated in vacuo to yield the“Generic Secondary Amines” hydrazine of Formula XIII. If needed the“Generic Secondary Amines” hydrazine can be further purified bycrystallization, distillation at reduced pressure, or liquidchromatography.

[0303] In another synthetic scheme (Reduction Method-2), which ispreferred when Z is a single bond or carbon, the “Generic Imine” ofFormula XII is slurried in a lower alcohol such as ethanol, methanol orlike solvent at 0-10° C. and solid sodium borohydride is added inbatches over 5-10 minutes at 0-10° C. with stirring. The reactionmixture is stirred below 10° C. for 30-90 minutes and then is warmedgradually to 15-30° C. After about 1-10 hours, the mixture is cooled andacid is added until the aqueous layer was just acidic (pH 5-7).

[0304] Isolation of the desired product can be accomplished, forexample, by extracting the aqueous layer twice with a solvent, such asdiethyl ether or methylene chloride, that is immiscible with water. Thecombined solvent extract is washed with saturated brine, dried with adrying agent such as anhydrous MgSO4, and concentrated in vacuo to yieldthe “Generic Secondary Amines” amine, aniline, or amine of Formula XIII.If needed the “Generic Secondary Amines” amine, aniline, or aminederivative can be further purified by crystallization, distillation atreduced pressure, or liquid chromatography.

[0305] In yet another synthetic scheme (Reduction Method-3), which ispreferred when Z is an oxygen, the “Generic Imine” oxime of Formula XIIis slurried in a lower alcohol solvent such methanol or like solvent at0-10° C. and acidified to a pH less than 4. Solid sodiumcyanoborohydride is added in batches over 30-90 minutes at 0-20° C. withstirring and addition of a suitable organic or mineral acid to keep thepH at or below 4. The reaction mixture is stirred and warmed graduallyto about 20-25° C. After about 1-10 hours, the mixture is cooled andbase added until the mixture was just slightly alkaline.

[0306] Isolation of the desired product can be accomplished, forexample, by removing the methanol or other low boiling solvent in vacuo.The residue is slurried with water and aqueous-organic mixture isextracted twice with a solvent, such as diethyl ether or methylenechloride, that is immiscible with water. The combined solvent extract iswashed with saturated brine, dried with a drying agent such as anhydrousMgSO₄, and concentrated in vacuo to yield the “Generic Secondary Amines”hydroxylamine of Formula XIII. If needed the “Generic Secondary Amines”hydroxylamine can be further purified by crystallization, distillationat reduced pressure, or liquid chromatography.

[0307] The “Generic Secondary Amines” of Formula XIII can also beprepared, according to Scheme 1 by two alkylation procedures based onthe nucleophilic substitution of bromides by amines. In one procedure,“Generic Amine-1” of Formula X is reacted with “Generic Bromide-1” ofFormula XXI. In another alkylation procedure, “Generic Amine-2” ofFormula XXII is reacted together with “Generic Bromide-2” of FormulaXXIII.

[0308] In one synthetic alkylation scheme (Alkylation Method-1), a“Generic Amine-1” of Formula X is reacted with a “Generic Bromide-2” ofFormula XXIII as described in Vogel's Textbook of Practical OrganicChemistry, Fifth Edition, 1989, pages 902 to 905 and references citedtherein all of which are incorporated herein by reference. In thisprocedure, the “Generic Amine-1” is placed in a reaction vessel equippedwith a reflux condenser with the capability to either cool or heat thevessel as dictated by the reaction. A suitable “Generic Amine-1” will beselected from primary amine and primary aromatic amine classes ofcompounds. Cooling may be needed and used should the reaction provestrongly exothermic. Heating may be needed and used to drive thereaction to completion. A suitable solvent may also be used to dissolvethe “Generic Amine-1”. Suitable solvents are hydrocarbons such astoluene, hexane, xylene, and cyclohexane, ethers, amides such asdimethylformamide, esters such as ethyl acetate, ketones such asacetone, and nitrites such as acetonitrile or mixtures of two or more ofthese solvents. A suitable base is also added to the reaction vessel.Suitable bases include cesium carbonate, calcium carbonate, sodiumcarbonate and sodium bicarbonate. The base will normally be added in atleast a stoichmetric quantity compared to the “Generic Amine-1” so as toneutralize liberated acid as it forms.

[0309] The “Generic Bromide-1” of Formula XXI is then added to thereaction vessel in portions so as to minimize the rate of heat evolutionand minimize the concentration of the “Generic Bromide-1”. The “GenericBromide-1” will be selected from primary and secondary organic alkyl andsubstituted alkyl halide compounds. The halide will preferrably be abromide although iodides and chlorides may also be generally used. Oneof skill in the art will also be able to readily select and utilizeorganic alkyl and substituted alkyl compounds containing readilydisplaceable primary and secondary groups such as tosylates, mesylates,triflates, and the like. Alternately, the halides can be generallyprepared from the corresponding alcohols by reaction with, for example,concentrated hydrohalic acids such as HBr or by reaction with phosphorustrihalides such as PBr₃ as described in Fieser and Fieser in Reagentsfor Organic Synthesis, Volume 1, John Wiley & Sons, which areincorporated herein by reference. The appropriate alcohols can beconverted to tosylates, mesylates, and triflates using proceduresdescribed below.

[0310] Addition of the “Generic Bromide-1” is carried out over a periodof a few minutes to several hours at temperatures between 0 and 150° C.Preferrably, the addition will take 30-120 minutes at a temperature of 0to 50° C. The reaction can be stirred until completion. Completion canbe monitored, for example, spectroscopically using nuclear magneticresonance or chromatographically using thin layer, liquid, or gaschromatographic procedures. If the reaction does not proceed tocompletion, the reactants may be heated until completion is obtained andverified.

[0311] Isolation of the desired product can be accomplished, forexample, when a water immiscible solvent was used for the reaction, byadding water to the finished reaction. Additional base such as sodiumcarbonate can be added to ensure the reaction is basic (pH of 9 to 11).The organic layer containing the “Generic Secondary Amine” is washedwith saturated brine, dried with a drying agent such as anhydrous MgSO₄,and concentrated in vacuo to yield the “Generic Secondary Amine” amine,aniline, or amine of Formula XII. If needed the “Generic SecondaryAmine” amine, aniline, or amine derivative can be further purified bycrystallization, distillation at reduced pressure, or liquidchromatography.

[0312] In a second synthetic alkylation scheme (Alkylation Method-2), a“Generic Amine-2” of Formula XXII is reacted with a “Generic Bromide-2”of Formula XXIII in a method employing palladium catalyzedcarbon-nitrogen bond formation. Suitable procedures for this conversionare described in Wagaw and Buchwald, J. Org. Chem.(1996), 61, 7240-7241,Wolfe, Wagaw and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, andWolfe and Buchwald, Tetrahedron Letters (1997), 38(36), 6359-6362 andreferences cited therein all of which are incorporated herein byreference. The preferred “Generic Bromide-2” of Formula XXIII aregenerally aryl bromides, aryl triflates, and heteroaryl bromides.

[0313] The “Generic Amine-1” and “Generic Amine-2” amines,hydroxylamines, and hydrazines, the “Generic Carbonyl Compound”aldehydes, ketones, hydrazones, and oximes, and “Generic Bromide-1” and“Generic Bromide-2” halides, tosylates, mesylates, triflates, andprecursor alcohols required to prepare the “Generic Secondary Amine”compounds are available from commercial sources, can be prepared by oneskilled in the art from published procedures, and/or can be obtainedusing specific procedures shown in Schemes 42, 43, and 44. Commercialsources include but are not limited to Aldrich Chemical, TCI-America,Lancaster-Synthesis, Oakwood Products, Acros Organics, and MaybridgeChemical. Disclosed procedures for “Generic Amine” amines,hydroxylamines, and hydrazines include Sheradsky and Nov, J. Chem. Soc.,Perkin Trans.1 (1980), (12), 2781-6; Marcoux, Doye, and Buchwald, J. Am.Chem. Soc. (1997), 119, 1053-9; Sternbach and Jamison, Tetrahedron Lett.(1981), 22(35), 33314; U.S. Pat. No. 5,306,718; EP No. 314435; WO No.9001874; WO No. 9002113; JP No. 05320117; WO No. 9738973; Swiss PatentNo. CH 441366; U.S. Pat. Nos. 3,359,316 and 3,334,017; and referencescited therein which are incorporated herein by reference. Representativespecific “Generic Secondary Amine” of Formula XIII compounds useful forthe preparation of compounds of the present invention are listed inTables 3, 4, and 5. TABLE 3 Structure of “Secondary Phenyl Amine”Reagents.

Secondary Phenyl Amine (XIIIA) Reagent Number R₄ R₅ R₆ R₇ R₉ R₁₀ R₁₁ YR₁₄  1N H phenoxy H H H OCF₂CF₂H H CH H  2N H OCF₃ H H H OCF₂CF₂H H CH H 3N F H H F H OCF₂CF₂H H CH H  4N H F H H H OCF₂CF₂H H CH H  5N Hphenoxy H H H OCF₃ H CH H  6N H OCF₃ H H H OCF₃ H CH H  7N H H phenyl HH OCF₃ H CH H  8N H phenyl H H H OCF₃ H CH H  9N H H H H H OCF₃ H CH H10N H Br H H H OCF₃ H CH H 11N H CF₃ F H H CF₃ H CH H 12N H CH₃ H H HCF₃ H CH H 13N H CF₃ H H H CF₃ H CH H 14N H CH₃ H H H OCF₃ H CH H 15N HF F H H OCF₃ H CH H 16N H Br H H H CF₃ H CH H 17N H CF₃ F H H OCF₃ H CHH 18N H F H H H OCF₃ H CH H 19N H Cl H H H OCF₃ H CH H 20N H F H H H CF₃H CH H 21N H F F H H CF₃ H CH H 22N H Cl H H H CF₃ H CH H 23N H F H H Hphenoxy H CH H 24N H CF₃ Cl H H CH₃ H CH H 25N H CF₃ F H H CH₃ H CH H26N H H H H H CF₃ H CH H 27N F F H H H CF₃ H CH H 28N H H OCH₃ H H CF₃ HCH H 29N H F F H H CH₃ H CH H 30N H OCH₃ H H H CH₃ H CH H 31N H H CH₃ HH H H CH H 32N H Cl H H H H H CH H 33N H F H H H F H CH H 34N H H OCH₃ HH CH₃ H CH H 35N H H H H H H H CH H 36N H H CH₃ H H CH₃ H CH H 37N H HCl H H H H CH H 38N H F H H H 3-CF₃-phenoxy H CH H 39N H F H H H4-CH₃O-phenoxy H CH H 40N H F H H H 4-Cl-phenoxy H CH H 41N H F H H H HH CH H 42N H F H H H CH₃ H CH H 43N H F H F H CH₃ H CH H 44N F F H H HCH₃ H CH H 45N H Cl H H H CH₃ H CH H 46N H CH₃ H H H CH₃ H CH H 48N H HCH₃ H H CF₃ H CH H 51N H H CH₃ H H F H CH H 52N H CF₃ H H H F H CH H 53NH CF₃ H H H CH₃ H CH H 54N H OCH₃ H H H CF₃ H CH H 56N H H CH₃ H H CF₃ HCH H 57N H phenoxy H H H H OCF₃ CH H 58N H H H H H H OCF₃ CH H 59N H OCFH H H H OCF₃ CH H 60N H CF₃ F H H H CF₃ CH H 61N H H OCH₃ H H H CF₃ CH H62N H CH₃ H H H H CF₃ CH H 63N H Cl H H H H CF₃ CH H 64N H CF₃ H H H HOCF₃ CH H 65N H F H H H H OCF₃ CH H 66N H F H F H H OCF₃ CH H 67N H Br HH H H OCF₃ CH H 68N H Cl H H H H OCF₃ CH H 69N H F F H H H OCF₃ CH H 70NH F H H H H phenyl CH H 71N H CH₃ H H H H OCF₃ CH H 72N H F F H H H CF₃CH H 73N H Cl H H H H CH₃ CH H 74N H OCH₃ H H H H CH₃ CH H 75N H F H H HH CH₃ CH H 76N F F H H H H OCF₃ CH H 78N H H OCH₃ H H H CH₃ CH H 79N H HCH₃ H H H CH₃ CH H 80N H CH₃ H H H H CH₃ CH H 82N H F F H H H CH₃ CH H83N H F H F H H CH₃ CH H 84N F F H H H H CH₃ CH H 85N F CF₃ H H H H CH₃CH H 86N H H CH₃ H H H CF₃ CH H 88N H CF₃ H H H H CH₃ CH H 90N H H CF₃ HH H CH₃ CH H 92N H CF₃ F H H H CH₃ CH H

[0314] TABLE 4 Structure of “Secondary Phenyl Amine” Reagents (Z iscovalent bond; there is no R₁₅ substituent; R₄ and R₁₃ equal H).

Secondary Phenyl Amine (XIII-A) Spacer Rgnt. Bond No. R₅ R₆ R₇ R₈ Y R₁₄R₉ R₁₀ R₁₁ R₁₂ Spacer Points  93N Br H H CH H H H OCF₃ —O— R₈ + R₉  94NOCF₃ H H CH H H H OCF₃ — R₈ + R₉  95N Br H H C H OCF₃ H H ═CH— R₈ + R₁₄ 96N OH OH H H CH H H C₆H₅O H H none none  97N C₆H₅O H H H CH H H OH OHH none none  98N 3-pyridyl H H H CH H H CF₃ H H none none  99N SO₂N H HH CH H H OCF₃ H H none none (CH₃)₂ 100N SO₂CH₃ H H H CH H H OCF₃ H Hnone none 101N C₆H₅O H H H CH H H C₆H₅O H H none none 102N CF₃O H H H CHH H C₆H₅O H H none none 103N C₆H₅ H H H CH H H C₆H₅O H H none none 104NH C₆H₅ H H CH H H C₆H₅O H H none none 105N C₆H₅O H H H CH H H 4-Cl—C₆H₄OH H none none 106N CF₃O H H H CH H H 4-Cl—C₆H₄O H H none none 107N C₆H₅OH H H CH H H 3,4-Cl—C₆H₃O H H none none 108N CF₃O H H H CH H H3,4-Cl—C₆H₃O H H none none 109N CF₃O H H H CH H H 3,5-Cl—C₆H₃O H H nonenone 110N CF₃O H H H CH H H 3-CH₃O— H H none none C₆H₄O 111N CF₃O H H HCH H H H 3-CH₃O— H none none C₆H₄O 112N CF₃O H H H CH H H 3-CF₃—C₆H₄O HH none none 113N CF₃O H H H CH H H C₆H₅—CH₂O H H none none 114N CF₃O H HH CH H H C₆H₅—CH₂O CH₃O H none none 115N CF₃O H H H CH H H C₆H₅—CH₂OC₆H₅— H none none CH₂O 116N CF₃O H H H CH H H ethoxy H H none none 117NCF₃O H H H CH H H CH₃CO₂ H H none none 118N CF₃O H H H CH H H HOCH₂— H Hnone none CH₂O 119N CF₃O H H H CH H H

H H none none 120N CF₃O H H H CH H H R₁₀ + R₁₁ = OCH₂O H none none 121NCF₃O H H H CH H H R₁₀ + R₁₁ = OCH₂CH₂O H none none 122N CF₃O H H H CH HH CH₃O CH₃O H none none 123N CF₃O H H H CH H H ethoxy CH₃O H none none124N CF₃O H H H CH H H ethoxy ethoxy H none none 125N CF₃O H H H CH H HCH₃CO₂ CH₃CO₂ H none none 126N CF₃O H H H CH H H CH₃O CH₃CO₂ H none none127N CF₃O H H H CH H H n-butoxy H H none none 128N CF₃O H H H CH H HCH₃O H H none none 129N CF₃O H H H CH H H H CH₃O H none none 130N CH₃O HH H CH H H CH₃O H H none none 131N CH₃O H H H CH H H H CF₃O H none none132N CF₃O H H H CH H H H ethoxy H none none 133N CF₃O H H H CH H H Hn-propoxy H none none 134N C₆H₅—CH₂O H H H CH H H CF₃O H H none none135N C₆H₅—CH₂O H H H CH H H C₆H₅O H H none none 136N ethoxy H H H CH H HCF₃O H H none none 137N R₅ + R₆ = OCH₂O H H CH H H CF₃O H H none none138N R₅ + R₆ = OCH₂O H H CH H H C₆H₅O H H none none 139N R₅ + R₆ =OCH₂CH₂O H H CH H H CF₃O H H none none 140N CH₃O CH₃O H H CH H H CF₃O HH none none 141N R₅ + R₆ = OCH₂CH₂CH₂O H H CH H H CF₃O H H none none142N cyclo CH₃O H H CH H H CF₃O H H none none pentoxy 143N H C₆H₅O H HCH H H CF₃O H H none none 144N CH₃O CH₃O CH₃O H CH H H CF₃O H H nonenone 145N H CF₃O H H CH H H CF₃O H H none none 146N H Benzyl H H CH H HCF₃O H H none none 147N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCH₂CH₂O H nonenone 148N H CF₃O H H CH H H CF₃ H H none none 149N C₆H₅O H H H CH H HCF₃ H H none none 150N C₆H₅ H H H CH H H CF₃ H H none none 151N H C₆H₅ HH CH H H CF₃ H H none none 152N CN H H H CH H H CF₃ H H none none 153N HOCF₃ H H CH H H CF₃ H H none none 154N OCF₃ H H H CH H H H CF₃ H nonenone 155N C₆H₅O H H H CH H H H CF₃ H none none 156N C₆H₅ H H H CH H H HCF₃ H none none 157N H C₆H₅ H H CH H H H CF₃ H none none 158N CN H H HCH H H H CF₃ H none none 159N OCF₃ H H H CH H H H CF₃ H none none 160NCF₃ H H H CH H H H C₆H₅ H none none 161N CF₃ H H H CH H H 3-CF₃— H Hnone none C₆H₅O 162N CF₃ H H H CH H H C₆H₅O H H none none 163N CF₃ H H HCH H H CF₃O H H none none 164N H CF₃ H H CH H H H C₆H₅ H none none 165NH CF₃ H H CH H H 3-CF₃— H H none none C₆H₅O 166N H CF₃ H H CH H H CF₃O HH none none 167N H CF₃ H H CH H H C₆H₅O H H none none 168N CF₃ H CF₃ HCH H H CF₃O H H none none 169N CF₃ H CF₃ H CH H H C₆H₅O H H none none170N CF₃O H H H CH H H CF₃ H CF₃ none none 171N C₆H₅O H H H CH H H CF₃ HCF₃ none none 172N H C₆H₅O H H CH H H C₆H₅O H H none none 173N H CF₃O HH CH H H CF₃O H H none none 174N H CF₃O H H CH H H H C₆H₅O H none none175N C₆H₅O H H H CH H H H C₆H₅O H none none 176N H C₆H₅O H H CH H H HOCF₃ H none none 177N H C₆H₅O H H CH H H H C₆H₅O H none none 178N C₆H₅OH H H CH H H H CN H none none 179N C₆H₅O H H H CH H H CN H H none none180N C₆H₅O H H H CH H H NO₂ H H none none 181N C₆H₅O H H H CH H H H NO₂H none none 182N C₆H₅O H H H CH H H H SO₂CH₃ H none none 183N C₆H₅O H HH CH H H H 2-NO₂-4- H none none Cl—C₆H₃O 184N C₆H₅O H H H CH H H4-Cl—C₆H₄O H H none none 185N C₆H₅O H H H CH H H 3,4-Cl—C₆H₃O H H nonenone 186N C₆H₅O H H H CH H H 3-CF₃— H H none none C₆H₃O 187N C₆H₅O H H HCH H H 3,5-Cl—C₆H₃O H H none none 188N C₆H₅O H H H CH H H H CH₃O H nonenone 189N C₆H₅O H H H CH H H H CO₂CH₃ H none none 190N C₆H₅O H H H CH HH 3-CH₃O H H none none C₆H₅O 191N C₆H₅O H H H CH H H 4-CH₃O H H nonenone C₆H₅O 193N C₆H₅O H H H CH H H CO₂CH₃ H H none none 194N CN H H H CHH H OCF₃ H H none none 195N NO₂ H H H CH H H OCF₃ H H none none 196N HCN H H CH H H OCF₃ H H none none 197N H NO₂ H H CH H H OCF₃ H H nonenone 198N SO₂CH₃ H H H CH H H OCF₃ H H none none 199N H SO₂CH₃ H H CH HH OCF₃ H H none none 200N H 4-F—C₆H₅ H H CH H H OCF₃ H H none none SO2201N SO₂N H H H CH H H OCF₃ H H none none (CH₃)₂ 202N H SO₂N H H CH H HOCF₃ H H none none (CH₃)₂ 203N H CONH₂ H H CH H H OCF₃ H H none none204N H CONH— H H CH H H OCF₃ H H none none C₆H₅ 205N H CO₂CH₃ H H CH H HOCF₃ H H none none 206N H CO₂C₄H₉ H H CH H H OCF₃ H H none none 207N H4-Cl—C₆H₅ H H CH H H C₆H₅O H H none none 208N H 4-CF₃O— H H CH H H CF₃OH H none none C₆H₅ 209N 4-F—C₆H₄O H H CH H H CF₃O H H none none 210NC₆F₅O H H H CH H H CF₃O H H none none 211N H 4-F—C₆H₅ H H CH H H CF₃O HH none none 212N H 4-CN—C₆H₅ H H CH H H CF₃O H H none none 213N H4-C₆H₅— H H CH H H CF₃O H H none none C₆H₅ 214N C₆H₅O H H H CH CH₃ HCF₃O H H none none 215N C₆H₅O H H H CH CH₃ H NO₂ H H none none 216NC₆H₅O H H H CH CH₃ H H CN H none none 217N C₆H₅O H H H CH 3-CF₃ H CF₃ HH none none C₆H₅ 218N C₆H₅O H H H CH C₆H₅ H H C₆H₅ H none none 219NC₆H₅O H H H CH C₆H₅ H CF₃ H H none none 220N C₆H₅O H H H CH CH₃ H F H Hnone none 221N C₆H₅O H H H CH CF H H H H none none 222N bond to —O—of R₆aryl group

H H CH H H CF₃O H H none none 223N to CH₂ of R₆ aryl group

H H CH H H CF₃O H H none none 224N C₆H₅O H H H CH H H OCF₂CF₂H H H nonenone 225N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 226N 4-F—C₆H₅OH H H CH H H OCF₂CF₂H H H none none 227N 3,4-Cl— H H H CH H H OCF₂CF₂H HH none none C₆H₅O 228N H C₆H₅ H H CH H H OCF₂CF₂H H H none none 229N H4-Cl—C₆H₅ H H CH H H OCF₂CF₂H H H none none 230N H 4-F—C₆H₅ H H CH H HOCF₂CF₂H H H none none 231N H 4-Br—C₆H₅ H H CH H H OCF₂CF₂H H H nonenone 232N 4-Br—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 233N C₆H₅O H HH CH H H OCF₂CF₃ H H none none 234N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₃ H Hnone none 235N 4-F—C₆H₅O H H H CH H H OCF₂CF₃ H H none none 236N 3,4-Cl—H H H CH H H OCF₂CF₃ H H none none C₆H₅O 237N H C₆H₅ H H CH H H OCF₂CF₃H H none none 238N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₃ H H none none 239N H4-F—C₆H₅ H H CH H H OCF₂CF₃ H H none none 240N H 4-Br—C₆H₅ H H CH H HOCF₂CF₃ H H none none 241N 4-Br—C₆H₅O H H H CH H H OCF₂CF₃ H H none none242N C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 243N 4-Cl—C₆H₅O H H HCH H H OCCl₂CCl₂H H H none none 244N 4-F—C₆H₅O H H H CH H H OCCl₂CCl₂H HH none none 245N 3,4-Cl— H H H CH H H OCCl₂CCl₂H H H none none C₆H₅O246N H C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 247N H 4-Cl—C₆H₅ H H CHH H OCCl₂CCl₂H H H none none 248N H 4-F—C₆H₅ H H CH H H OCCl₂CCl₂H H Hnone none 249N H 4-Br—C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 250N4-Br—C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 251N C₆H₅O H H H CH H HOCCl₂CCl₃ H H none none 252N 4-Cl—C₆H₅O H H H CH H H OCCl₂CCl₃ H H nonenone 253N 4-F—C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 254N 3,4-Cl— HH H CH H H OCCl₂CCl₃ H H none none C₆H₅O 255N H C₆H₅ H H CH H HOCCl₂CCl₃ H H none none 256N H 4-Cl—C₆H₅ H H CH H H OCCl₂CCl₃ H H nonenone 257N H 4-F—C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 258N H 4-Br—C₆H₅H H CH H H OCCl₂CCl₃ H H none none 259N 4-Br—C₆H₅O H H H CH H HOCCl₂CCl₃ H H none none 260N C₆H₅O H H H CH H H OCCl₂CF₃ H H none none261N 4-Cl—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 262N 4-F—C₆H₅O H H HCH H H OCCl₂CF₃ H H none none 263N 3,4-Cl— H H H CH H H OCCl₂CF₃ H Hnone none C₆H₅O 264N H C₆H₅ H H CH H H OCCl₂CF₃ H H none none 265N H4-Cl—C₆H₅ H H CH H H OCCl₂CF₃ H H none none 266N H 4-F—C₆H₅ H H CH H HOCCl₂CF₃ H H none none 267N H 4-Br—C₆H₅ H H CH H H OCCl₂CF₃ H H nonenone 268N 4-Br—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 269N C₆H₅O H HH CH H H OCF₂CCl₃ H H none none 270N 4-Cl—C₆H₅O H H H CH H H OCF₂CCl₃ HH none none 271N 4-F—C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 272N3,4-Cl— H H H CH H H OCF₂CCl₃ H H none none C₆H₅O 273N H C₆H₅ H H CH H HOCF₂CCl₃ H H none none 274N H 4-Cl—C₆H₅ H H CH H H OCF₂CCl₃ H H nonenone 275N H 4-F—C₆H₅ H H CH H H OCF₂CCl₃ H H none none 276N H 4-Br—C₆H₅H H CH H H OCF₂CCl₃ H H none none 277N 4-Br—C₆H₅O H H H CH H H OCF₂CCl₃H H none none 278N C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 279N4-Cl—C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 280N 4-F—C₆H₅O H HH CH H H OCF₂CF₂H OCF₂CF₂H H none none 281N 3,4-Cl— H H H CH H HOCF₂CF₂H OCF₂CF₂H H none none C₆H₅O 282N H C₆H₅ H H CH H H OCF₂CF₂HOCF₂CF₂H H none none 283N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H Hnone none 284N H 4-F—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 285NH 4-Br—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 286N 4-Br—C₆H₅O H HH CH H H OCF₂CF₂H OCF₂CF₂H H none none 287N C₆H₅O H H H CH H H OCF₃ OCF₃H none none 288N 4-Cl—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 289N4-F—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 290N 3,4-Cl— H H H CH H HOCF₃ OCF₃ H none none C₆H₅O 291N H C₆H₅ H H CH H H OCF₃ OCF₃ H none none292N H 4-Cl—C₆H₅ H H CH H H OCF₃ OCF₃ H none none 293N H 4-F—C₆H₅ H H CHH H OCF₃ OCF₃ H none none 294N H 4-Br—C₆H₅ H H CH H H OCF₃ OCF₃ H nonenone 295N 4-Br—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 296N C₆H₅O H H HCH H H OCF₂H OCF₂H H none none 297N 4-Cl—C₆H₅O H H H CH H H OCF₂H OCF₂HH none none 298N 4-F—C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 299N3,4-Cl— H H H CH H H OCF₂H OCF₂H H none none C₆H₅O 300N H C₆H₅ H H CH HH OCF₂H OCF₂H H none none 301N H 4-Cl—C₆H₅ H H CH H H OCF₂H OCF₂H H nonenone 302N H 4-F—C₆H₅ H H CH H H OCF₂H OCF₂H H none none 303N H 4-Br—C₆H₅H H CH H H OCF₂H OCF₂H H none none 304N 4-Br—C₆H₅O H H H CH H H OCF₂HOCF₂H H none none 305N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H nonenone 306N 4-Cl—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 307N4-F—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 308N 3,4-Cl— H HH CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 309N H C₆H₅ H H CH H H R₁₀ +R₁₁ = OCF₂CF₂O H none none 310N H 4-Cl—C₆H₅ H H CH H H R₁₀ + R₁₁ =OCF₂CF₂O H none none 311N H 4-F—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O Hnone none 312N H 4-Br—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none313N 4-Br—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 314N C₆H₅OH H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 315N 4-Cl—C₆H₅O H H H CHH H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 316N 4-F—C₆H₅O H H H CH H H R₁₀ +R₁₁ = OCCl₂CCl₂O H none none 317N 3,4-Cl— H H H CH H H R₁₀ + R₁₁ =OCCl₂CCl₂O H none none C₆H₅O 318N H C₆H₅ H H CH H H R₁₀ + R₁₁ =OCCl₂CCl₂O H none none 319N H 4-Cl—C₆H₅ H H CH H H R₁₀ + R₁₁ =OCCl₂CCl₂O H none none 320N H 4-F—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂OH none none 321N H 4-Br—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H nonenone 322N 4-Br—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none323N H H H H CH H H OH H H none none 324N H H H H CH H H OH OH H nonenone 325N H H H H CH H H H OH H none none 326N H H H H CH H H OCH₂CF₃ HH none none 327N H H H H CH H H H OCH₂CF₃ H none none 328N H H H H CH HH OCH₂CF₂CF₃ H H none none 329N H H H H CH H H OCH₂CH₂CF₃ H H none none330N H H H H CH H H OCH(CF₃)₃ H H none none 331N H 4-F—C₆H₅O H H CH H HH H H none none 332N 4-F—C₆H₅O H H H CH H H H H H none none 333N Hcyclo- H H CH H H H H H none none hexoxy 334N cyclo-hexoxy H H H CH H HH H H none none 335N H C(CH₃)₃ H H CH H H H H H none none 336N F H H HCH H H

bond to indicated phenyl carbon of R₁₀ subst. H none none

[0315] TABLE 5 Structure of “Secondary Phenyl Amine” Reagents (Y and Zeach equal CH; R₇, R₈, R₁₂, R₁₃, R₁₄, and R₁₅ each equal H).

Secondary Phenyl Amine (XIII-A) Reagent Number R₄ R₅ R₆ R₉ R₁₀ R₁₁  1DBH OCF₃ H H OCF₃ H  2DB H Cl H H H CF₃  3DB H Br H H OCF₃ H  4DB H Cl H HOCF₃ H  5DB H Cl H H CF₃ H  6DB H H Cl H CF₃ H  7DB H F H H OCF₃ H  8DBH H Cl H H CF₃  9DB H F H H H CF₃ 10DB H H F H H CF₃ 11DB F H H H H CF₃12DB H Cl H CF₃ H H 13DB H H Cl CF₃ H H 14DB Cl H H CF₃ H H 15DB H F HCH₃ H H 16DB H H F H H CH₃ 17DB H F H H CH₃ H 18DB F H H CH₃ H H 19DB HH F H CH₃ H 20DB F H H H H CH₃ 21DB F H H H CF₃ H 22DB Cl H H H CF₃ H23DB H F H CF₃ H H 24DB H H F CF₃ H H 25DB H F H H CF₃ H 26DB H H F HCF₃ H 27DB H OCF₃ H H H OCF₃

[0316] As summarized in the general Scheme 1 and specific descriptionsabove, Schemes 3, 4, 9, and 10 illustrate the principles of Scheme 1 forthe preparation of specifically substituted “Secondary HeteroarylAmines” (XIIIA-H) having 0 to 2 aryl groups and 0 to 2 aromaticheterocyclyl groups and “Secondary Phenyl Amines” (XIII-A) having twoaryl groups.

[0317] Synthetic Scheme 2 shows the preparation of the class ofcompounds of the present invention corresponding to Formula I-H(“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic PolycyclicAryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) wherein Aand Q are independently aryl and heteroaryl.

[0318] Derivatives of “Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-alkanols”, “Generic Polycyclic Aryland Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”,“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”, “Polycyclic Phenyl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-Alkanols”, and “Polycyclic Phenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”, wherein A and Qare independently aryl and heteroaryl, in which the hetero atom (—O—) isattached to an alkyl group removed from the amine by three or morecarbons are readily prepared by anion chemistry using Method B of Scheme2. The anion of “Generic Secondary Amine” amines, hydroxylamines, andhydrazines of Formula XIII are readily formed by dissolving the specificamine, hydroxylamine, or hydrazine in an aprotic solvent, such astetrahydrofuran, toluene, ether, dimethylformamide, anddimethylformanide, under anhydrous conditions. The solution is cooled toa temperature between −78 and 0° C., preferrably between −78 and −60° C.and the anion formed by the addition of at least one equivalent of astrong, aprotic, non-nucleophillic base such as NaH or n-butyllithiumunder an inert atmosphere for each acidic group present. Maintaining thetemperature between −78 and 0° C., preferrably between −78 and −60° C.,with suitable cooling, an appropriate alkyl halide, alkylbenzenesulfonate such as a alkyl tosylate, alkyl mesylate, alkyltriflate or similar alkylating reagent of the general structure:

[0319] where M is a readily displaceable group such as chloride,bromide, iodide, tosylate, triflate, and mesylate, X is oxy, and XXX isa chiral reagent in the indicated (R)-configuration. After allowing thereaction mixture to warm to room temperature, the reaction product isadded to water, neutralized if necessary, and extracted with awater-immiscible solvent such as diethyl ether or methylene chloride.The combined aprotic solvent extract is washed with saturated brine,dried over drying agent such as anhydrous MgSO4 and concentrated invacuo to yield crude Formula I-H (“Generic Polycyclic Aryl andHeteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”),Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), whereinA and Q are independently aryl and heteroaryl. This material ispurified, for example, by eluting through silica gel with 5-40% of amedium polar solvent such as ethyl acetate in a non-polar solvent suchas hexanes to yield Formula I-H (“Generic Polycyclic Aryl and Heteroaryl(R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP(“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”). Productsare tested for purity by HPLC. If necessary, Formula I-H (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic PolycyclicAryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compoundsare purified by additional chromatography or recrystallization. Productsare structurally confirmed by low and high resolution mass spectrometryand NMR. Examples of specific compounds prepared are summarized inTables 6 and 7.

[0320] Compounds of Formula (XXX), which can be used to prepare the“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanol” compounds of Tables 6 and 7, are givenin Table 2. Reagents 1 a and 2 a in Table 2 are prepared from thecorresponding alcohols. (R)-Chiral alcohol precursors to 1 a, 2 a, andsimilar alcohols that can be envisioned by one of inventive skill can beobtained from the corresponding racemic mixture of the R-enatiomer andS-enantiomer by separation procedures using preparative gaschromatography and high pressure liquid chromatography using chiralchromatographic columns. The tosylates of chiral alcohols and racemicmixtures are readily obtained by reacting the corresponding alcohol withtosyl chloride using procedures found in House's Modern SyntheticReactions, Chapter 7, W. A. Benjamin, Inc., Shriner, Fuson, and Curtinin The Systematic Indentification of Organic Compounds, 5th Edition,John Wiley & Sons, and Fieser and Fieser in Reagents for OrganicSynthesis, Volume 1, John Wiley & Sons, which are incorporated herein byreference. TABLE 6 Structure of Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n + 1)-Alkanols (Y is CH; R₈, R₉, R₁₂, R₁₃, and R₁₄are each H; Z is covalent bond and R₁₅ is absent).

Inhibitor Number Column1 + Column 2 Reagent Reagent R₁ n R₂ R₃ R₄ R₅ R₆R₇ R₁₀ R₁₁ 1A  1N CF₃ 3 H H H C₆H₅O H H OCF₂CF₂H H 1A  2N CF₃ 3 H H HOCF₃ H H OCF₂CF₂H H 1A  3N CF₃ 3 H H F H H F OCF₂CF₂H H 1A  4N CF₃ 3 H HH F H H OCF₂CF₂H H 1A  5N CF₃ 3 H H H C₆H₅O H H OCF₃ H 1A  6N CF₃ 3 H HH OCF₃ H H OCF₃ H 1A  7N CF₃ 3 H H H H phenyl H OCF₃ H 1A  8N CF₃ 3 H HH phenyl H H OCF₃ H 1A  9N CF₃ 3 H H H H H H OCF₃ H 1A 10N CF₃ 3 H H HBr H H OCF₃ H 1A 11N CF₃ 3 H H H CF₃ F H CF₃ H 1A 12N CF₃ 3 H H H CH₃ HH CF₃ H 1A 13N CF₃ 3 H H H CF₃ H H CF₃ H 1A 14N CF₃ 3 H H H CH₃ H H OCF₃H 1A 15N CF₃ 3 H H H F F H OCF₃ H 1A 16N CF₃ 3 H H H Br H H CF₃ H 1A 17NCF₃ 3 H H H CF₃ F H OCF₃ H 1A 18N CF₃ 3 H H H F H H OCF₃ H 1A 19N CF₃ 3H H H Cl H H OCF₃ H 1A 20N CF₃ 3 H H H F H H CF₃ H 1A 21N CF₃ 3 H H H FF H CF₃ H 1A 22N CF₃ 3 H H H Cl H H CF₃ H 1A 23N CF₃ 3 H H H F H Hphenoxy H 1A 24N CF₃ 3 H H H CF₃ Cl H CH₃ H 1A 25N CF₃ 3 H H H CF₃ F HCH₃ H 1A 26N CF₃ 3 H H H H H H CF₃ H 1A 27N CF₃ 3 H H F F H H CF₃ H 1A28N CF₃ 3 H H H H OCH₃ H CF₃ H 1A 29N CF₃ 3 H H H F F H CH₃ H 1A 30N CF₃3 H H H OCH₃ H H CH₃ H 1A 31N CF₃ 3 H H H H CH₃ H H H 1A 32N CF₃ 3 H H HCl H H H H 1A 33N CF₃ 3 H H H F H H F H 1A 34N CF₃ 3 H H H H OCH₃ H CH₃H 1A 35N CF₃ 3 H H H H H H H H 1A 36N CF₃ 3 H H H H CH₃ H CH₃ H 1A 37NCF₃ 3 H H H H Cl H H H 1A 38N CF₃ 3 H H H F H H 3-CF₃- H phenoxy 1A 39NCF₃ 3 H H H F H H 4-CH₃O- H phenoxy 1A 40N CF₃ 3 H H H F H H 4-Cl- Hphenoxy 1A 41N CF₃ 3 H H H F H H H H 1A 42N CF₃ 3 H H H F H H CH₃ H 1A43N CF₃ 3 H H H F H F CH₃ H 1A 44N CF₃ 3 H H F F H H CH₃ H 1A 45N CF₃ 3H H H Cl H H CH₃ H 1A 46N CF₃ 3 H H H CH₃ H H CH₃ H 1A 48N CF₃ 3 H H H HCH₃ H CF₃ H 1A 51N CF₃ 3 H H H H CH₃ H F H 1A 52N CF₃ 3 H H H CF₃ H H FH 1A 53N CF₃ 3 H H H CF₃ H H CH₃ H 1A 54N CF₃ 3 H H H OCH₃ H H CF₃ H 1A56N CF₃ 3 H H H H CH₃ H CF₃ H 1A 57N CF₃ 3 H H H C₆H₅O H H H OCF₃ 1A 58NCF₃ 3 H H H H H H H OCF₃ 1A 59N CF₃ 3 H H H OCF₃ H H H OCF₃ 1A 60N CF₃ 3H H H CF₃ F H H CF₃ 1A 61N CF₃ 3 H H H H OCH₃ H H CF₃ 1A 62N CF₃ 3 H H HCH₃ H H H CF₃ 1A 63N CF₃ 3 H H H Cl H H H CF₃ 1A 64N CF₃ 3 H H H CF₃ H HH OCF₃ 1A 65N CF₃ 3 H H H F H H H OCF₃ 1A 66N CF₃ 3 H H H F H F H OCF₃1A 67N CF₃ 3 H H H Br H H H OCF₃ 1A 68N CF₃ 3 H H H Cl H H H OCF₃ 1A 69NCF₃ 3 H H H F F H H OCF₃ 1A 70N CF₃ 3 H H H F H H H phenyl 1A 71N CF₃ 3H H H CH₃ H H H OCF₃ 1A 72N CF₃ 3 H H H F F H H CF₃ 1A 73N CF₃ 3 H H HCl H H H CH₃ 1A 74N CF₃ 3 H H H OCH₃ H H H CH₃ 1A 75N CF₃ 3 H H H F H HH CH₃ 1A 76N CF₃ 3 H H F F H H H OCF₃ 1A 78N CF₃ 3 H H H H OCH₃ H H CH₃1A 79N CF₃ 3 H H H H CH₃ H H CH₃ 1A 80N CF₃ 3 H H H CH₃ H H H CH₃ 1A 82NCF₃ 3 H H H F F H H CH₃ 1A 83N CF₃ 3 H H H F H F H CH₃ 1A 84N CF₃ 3 H HF F H H H CH₃ 1A 85N CF₃ 3 H H F CF₃ H H H CH₃ 1A 86N CF₃ 3 H H H H CH₃H H CF₃ 1A 88N CF₃ 3 H H H CF₃ H H H CH₃ 1A 90N CF₃ 3 H H H H CF₃ H HCH₃ 1A 92N CF₃ 3 H H H CF₃ F H H CH₃

[0321] TABLE 7 Structure of Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n + 1)-A1kanols (Y and Z are each CH; R₈, R₉, R₁₂,R₁₃, R₁₄ and R₁₅ are each H).

Inhibitor Number Column 1 + Column 2 Reagent Reagent R₁ n R₂ R₃ R₄ R₅ R₆R₉ R₁₀ R₁₁ 1A  1DB CF₃ 3 H H H OCF₃ H H OCF₃ H 1A  2DB CF₃ 3 H H H Cl HH H CF₃ 1A  3DB CF₃ 3 H H H Br H H OCF₃ H 1A  4DB CF₃ 3 H H H Cl H HOCF₃ H 1A  5DB CF₃ 3 H H H Cl H H CF₃ H 1A  6DB CF₃ 3 H H H H Cl H CF₃ H1A  7DB CF₃ 3 H H H F H H OCF₃ H 1A  8DB CF₃ 3 H H H H Cl H H CF₃ 1A 9DB CF₃ 3 H H H F H H H CF₃ 1A 10DB CF₃ 3 H H H H F H H CF₃ 1A 11DB CF₃3 H H F H H H H CF₃ 1A 12DB CF₃ 3 H H H Cl H CF₃ H H 1A 13DB CF₃ 3 H H HH Cl CF₃ H H 1A 14DB CF₃ 3 H H Cl H H CF₃ H H 1A 15DB CF₃ 3 H H H F HCH₃ H H 1A 16DB CF₃ 3 H H H H F H H CH₃ 1A 17DB CF₃ 3 H H H F H H CH₃ H1A 18DB CF₃ 3 H H F H H CH₃ H H 1A 19DB CF₃ 3 H H H H F H CH₃ H 1A 20DBCF₃ 3 H H F H H H H CH₃ 1A 21DB CF₃ 3 H H F H H H CF₃ H 1A 22DB CF₃ 3 HH Cl H H H CF₃ H 1A 23DB CF₃ 3 H H H F H CF₃ H H 1A 24DB CF₃ 3 H H H H FCF₃ H H 1A 25DB CF₃ 3 H H H F H H CF₃ H 1A 26DB CF₃ 3 H H H H F H CF₃ H1A 27DB CF₃ 3 H H H OCF₃ H H H OCF₃

[0322] Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated I-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compoundscan also be prepared using Method B of Scheme 2 through the use ofracemic (XXX) as described followed by preparative separation of theR-enantiomer from the S-enatiomer using chiral chromatographicprocedures such as preparative gas chromatography and high pressureliquid chromatography using readily available chiral chromatographiccolumns and procedures.

[0323] A preferred procedure for Formula I-HP (“Generic Polycyclic Aryland Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”),Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”), and Formula I-CP (“Polycyclic Phenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds is thenovel inventive Method A of Scheme 2. (R)-Chiral oxirane reagents usefulin Method A are exemplified, but not limited to those in Table 1.Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds are prepared by reacting“Generic Secondary Amine” amines, hydroxylamines, and hydrazines ofFormula XIII with (R)-chiral oxiranes of the type listed in Table 1 andrepresented by the general structure:

[0324] Oxiranes having a specific stereochemical arrangement of R₁, R₂and R₃ can be prepared using chiral procedures such as those publishedin 1995 by Ramachandran, Gong, and Brown in the Journal of OrganicChemistry, Vol. 60, pages 41 to 46; cited references also detailalternate procedures to prepare chiral and achiral epoxides, which areincorporated herein by reference. For example, the specific preparationof R-(+)-1,1,1-trifluoro-2,3-epoxypropane,

[0325] using a procedure adopted from H. C. Brown et al. (J. Org Chem.60, 41-46, (1995)), is accomplished as described in Example 4. Many ofthe epoxides summarized in Table 1 can be prepared in the(R)-configuration using procedures analogous to that given above forR-(+)-1,1,1-trifluoro-2,3-epoxypropane.

[0326] In some cases, achiral oxiranes of (XX) can be prepared from thecorresponding alkenes by reaction of epoxidation reagents such asmeta-chloroperbenzoic acid (MCPBA) and similar type reagents readilyselectable by a person of skill-in-the-art with alkenes. Fieser andFieser in Reagents for Organic Synthesis, John Wiley & Sons provides,along with cited references, numerous suitable epoxidation reagents andreaction conditions, which are incorporated herein by reference. Theseachiral oxiranes can be reacted in an identical manner to that describedfor (R)-chiral oxiranes with “Generic Secondary Amine” amines,hydroxylamines, and hydrazines of Formula XIII to afford racemiccompounds structurally identical to those of Formula I-HP, FormulaI-HPC, and Formula I-C but with the corresponding (S) chiralconfiguration present in an equivalent amount. Formula I-HP (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds can be obtained bypreparative chiral chromatography of said racemic mixtures to obtain the(R)-chiral configuration of Formula I-HP, Formula I-HPC, and FormulaI-CP substantially free of the (S)-chiral configuration enantiomer.Alternatively, achiral oxiranes may be separated by chiral preparativechromatography into their respective (R)-Chiral and (S)-Chiralenantiomers and the (R)-Chiral enantiomer reacted to afford Formula I-HP(“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds.

[0327] A mixture of a “Generic Secondary Amine” amine, hydroxylamine, orhydrazine of Formula XIII and an excess of a halogenated oxirane of(R)-chiral configuration of Formula XX are stirred and heated to 40-90°C. for 5 to 48 hours in a tightly capped or contained reaction vessel.More preferrably, a Lewis acid such as a transition metal-based salts(for example, ytterbium triflate, hafnium triflate, scandium triflate,neodynium triflate, gadolium triflate, and zirconium triflate) inmethylene chloride, tetrahydrofuran, or, more preferrably, acetonitrileis added to speed up the reaction to a total time of 4 to 18 hours,improve yields, to permit the reaction temperature to be reduced to15-65° C., and to use a smaller excess of halogenated oxirane. When aLewis acid is used, the reaction should be carried out under inert,anhydrous conditions using a blanket of dry nitrogen or argon gas. Aftercooling to room temperature and testing the reaction mixture forcomplete reaction by thin layer chromatography or high pressure liquidchromatography (hplc), the reaction product is added to water andextracted with a water immiscible solvent such as diethyl ether ormethylene chloride. (Note: If the above analysis indicates that reactionis incomplete, heating should be resumed until complete with theoptional addition of more of the oxirane). The combined aprotic solventextract is washed with saturated brine, dried over drying agent such asanhydrous MgSO₄ and concentrated in vacuo to yield crude Formula I-HP(“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds. This material is purified byeluting through silica gel with 540% of a medium polar solvent such asethyl acetate in a non-polar solvent such as hexanes to yield FormulaI-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds. Products are tested forpurity by HPLC. If necessary, the Formula I-HP (“Generic Polycyclic Aryland Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”),Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds arepurified by additional chromatography or recrystallization. Products arestructurally confirmed by low and high resolution mass spectrometry andNMR. Examples of specific Formula I-HP (“Generic Polycyclic Aryl andHeteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”),Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compoundsprepared are summarized in the Examples 1 through 44, and Example Tables1 through 12. TABLE 1 Structure of (R)-Chiral Oxirane Reagents.

(XX) Reagent Number R₁ R₂ R₃ 1 CF₃ H H 2 CCl₃ H H 3 CF₃ CH₃ H 4 CF₃CF₂ HH 5 CF₃CF₂CF₂ H H 6 CF₃OCF₂CF₂ H H 7 CF₃CH₂ H H 9 CF₃ H CF₃ 11 CF₃ C₆H₅H 12 CCl₃ C₆H₅ H 13 CCl₃ Cyclopropyl H 14 CCl₃ CH₃ H 15 CCl₃ (CH₃)₂CH H16 CHCl₂ H H 18 CF₃ H CH₃ 27 CCl₃CH₂ H H 28 CBr₃CH₂ H H 29 CHBr₂CH₂ H H30 CBrCl₂ H H 31 CClF₂ H H 32 CCl₂F H H 33 CCl₃CCl₂ H H 43 FCH₂ H H 56CBrF₂CClFCH₂ H H 57 HCF₂CF₂OCH₂ H H

[0328] TABLE 2 Structure and Source of Alcohol and Glycol Reagents.

(XXX) Reagent Number R₁ n M R₂ R₃ X-R₁₆ Source of Reagent 1A CF₃ 3 OTs HH OH Chiral separation and then tosylation of alcohol from JustusLiebigs Ann. Chem. (1969), 720, 81-97. 2A CF₃CH₂CH₂ 3 OTs H H OH Chiralseparation and then tosylation of alcohol from Z. Naturforsch., B: Chem.Sci. (1997), 52 (3). 413-418

[0329] As summarized in the general Scheme 2 and specific descriptionsabove, Schemes 5, 6, 7, and 11 illustrate the principles of Scheme 2 forthe preparation of specifically substituted Formula I-C (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) having 2aryl groups, Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl(R)-Chiral Halogenated 1-Substitutedamino-2-propanols”) having twoaromatic substituents made up of 0 to 2 aryl groups and 0 to 2 aromaticheterocyclyl groups, and Formula I-HPC (“Polycyclic Aryl-Heteroaryl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) having twoaromatic substituents made up of 0 to 2 aryl groups and 0 to 2 aromaticheterocyclyl groups.

[0330] Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds can further be prepared in analternate manner to procedures disclosed above and in Schemes 1 to 7 and9 to 11. Schemes 45 to 50 detail such procedures to prepareaminopropanol compounds of the present invention by initial formation ofan halogenated, oxygen containing primary alkylamine XVL (“GenericSubstituted Alkylamine”). Said halogenated, oxygen containing primaryalkylamine XVL, formed in Schemes 45 and 48, is itself converted tosecondary amines, VLX-H (“Heteroaryl Alkyl Amine) and VLX (“Phenyl AlkylAmine”), using procedures disclosed above. Primary alkylamine XVL isfirst reacted with an aldehydic or ketonic carbonyl compound, XI-AH(“Heteroaryl Carbonyl”) and XI-A (“Phenyl Carbonyl”) with azeotropicdistillation to form imines, VL-H (“Heteroaryl Imine”) and VL (“PhenylImine”). Said imines VL-H and VL are then reduced with or without priorisolation by Reduction Methods 1, 2 or 3 as disclosed above and inSchemes 1, 3, and 9 to yield secondary amines, VLX-H (“Heteroaryl AlkylAmine) and VLX (“Phenyl Alkyl Amine”). Said secondary amine VLX-H can beconverted according to Schemes 46 and 47 to give Formula I-HP (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”) and Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”)and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds. Using Schemes 49 and 50, VLXcan be converted to Formula I-C (“Polycyclic Phenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds. Compounds ofthis invention in which one aromatic substituent is aryl and the otheraromatic substitutent is heteroaryl can be readily prepared by reactingVLX-H with an aralkyl bromide or aryl bromide instead of using anheteroaralkyl bromide or heteroaryl bromide as described in Schemes 46and 47. Similarly, compounds of this invention in which one aromaticsubstituent is aryl and the other aromatic substitutent is heteroarylcan be readily prepared by reacting VLX with an heteroaryl bromide orheteroaralkyl bromide instead of using an aryl bromide or an aralkylbromide as described in Schemes 49 and 50.

[0331] Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds can further be prepared in analternate manner to procedures disclosed above and in Schemes 1 to 7, 9to 11, and 45 to 50. Schemes 56,57, and 58 detail alternate proceduresto prepare (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”compounds of the present invention by initial formation of anhalogenated, oxygen containing secondary alkylamines VLX and VLXX(“Phenyl Alkylamines”) and VLXX-O (“Phenyl Oxy Alkylamines”). Saidsecondary alkylamines VLX and VLXX (“Phenyl Alkylamines”) and VLXX-O(“Phenyl Oxy Alkylamines”) can be converted according to Schemes 56,57,and 58 to Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl(R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC(“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds byreaction with appropriate aromatic halides such as aryl bromides andheteroaryl bromides as desired.

[0332] Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds can further be prepared in analternate manner to procedures disclosed above and in Schemes 1 to 7, 9through 11, 45 through 50, and 56 through 58. Another alternateprocedure to prepare “(R)-Chiral Halogenated1-Substitutedamino-2-propanols” compounds of the present invention canbe achieved by reacting secondary amines of Formula XIIIA-H (“SecondaryHeteroaryl Amines”) and Formula XIII-A (“Secondary Phenyl Amines”) withcertain cyclic sulfates. Cyclic sulfates useful in the preparation of“(R)-Chiral Halogenated 1-Substitutedamino-2-propanols” compounds ofFormulas I-HP, I-HPC, and I-CP have a halogenated or haloalkoxy carbonadjacent to the cyclic sulfate. Some cyclic sulfates useful for thepreparation of “(R)-Chiral Halogenated 1-Substitutedamino-2-propanols”compounds of Formulas I-HP, I-HPC, and I-CP have been described by K. P.M. Vanhessche and K. B. Sharpless in Chem. Eur. J, 1997, Vol. 3, No. 4,pages 517-522 and references cited therein.(2R)-(+)-3,3,3-Trifluoro-1,2-propanediol can be prepared as described inthe reference cited immediately above from 3,3,3-trifluoropropenefollowed by separation from the predominating(2S)-(−)-3,3,3-trifluoro-1,2-propanediol. Alternatively,(2R)-(+)-3,3,3-Trifluoro-1,2-propanediol can be prepared by hydrolysisof (2R)-(+)-3,3,3-Trifluoro-2,3-epxoypropane analogous to the proceduredescribed by described by McBee and Burton in J. Am. Chem. Soc., 1952,Vol. 74, page 3022. (2R)-(+)-3,3,3-Trifluoro-1,2-propanediol isconverted by reaction with a slight excess of sulfuryl chloride in thepresence of 2.5 molar equivalents of imidazole, methylene chloridesolvent, and at a temperature of −20 ° C. to give the desired(4R)-(+)4-trifluoromethyl-2,2-dioxo-1,3,2-dioxathiolane. Reaction ofother (R)-Chiral haloalkyl or haloalkoxyalkyl substituted1,2-ethanediols can afford the corresponding(4R)-substituted-2,2-dioxo-1,3,2-dioxathiolanes. Reaction of (4R)-(+)4trifluoromethyl-2,2-1,3,2-dioxathiolane or another(4R)-substituted-2,2-dioxo-1,3,2-dioxathiolane with a secondary amine ofFormula XIIIA-H (“Secondary Heteroaryl Amines”) and Formula XIII-A(“Secondary Phenyl Amines”) in an anhydrous polar, non-protic solventsuch as tetrahydrofuran or acetonitrile at 25-60 ° C. until the reactionis complete can afford the mono-sulfate ester of a compound of FormulasI-HP, I-HPC, and I-CP. Removal of the solvent followed by addition ofdiethyl ether and excess 20% aqueous sulfuric acid can lead to aprecipitant of the crude mono-sulfate ester of a compound of FormulasI-HP, I-HPC, and I-CP. This precipitant can be filtered, the solid canbe washed with ether, it can be resuspended in aqueous 20% sulfuricacid, and can be heated to 80-95 ° C. to give an aqueous solution of thesulfate salt of crude a compound of Formulas I-HP, I-HPC, and I-CP.Neutralization of the aqueous solution, extraction with a waterimmiscible solvent such as diethyl ether or methylene chloride, dryingthe organic solvent over anhydrous magnesium sulfate, and removal ofsolvent can afford a compound of Formulas I-HP, I-HPC, and I-CP.Compounds of Formulas I-HP, I-HPC, and I-CP can be purified as describedpreviously. By using a wide variety of (R)-Chiral diols, secondaryamines of Formula XIIIA-H (“Secondary Heteroaryl Amines”) and FormulaXIII-A (“Secondary Phenyl Amines”), and reaction conditions describedherein, a large variety of compounds of Formulas I-HP, I-HPC, and I-CPmay be preparable.

[0333] Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-alkanols”) and Formula I-C(“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), in which the halogenated hydroxycontaining alkyl side chain has three carbons between the amine andhydroxy group, can be prepared in a manner similar to proceduresdisclosed above and in Schemes 45 to 50. Schemes 30 to 35 detail suchprocedures to prepare 1-amino-3-butanol compounds of the presentinvention by initial formation of an halogenated, oxygen containingprimary alkylamine XL (“Generic Substituted Alkylamine”). Saidhalogenated, oxygen containing primary alkylamine XL, formed in Schemes30 and 33, is itself converted to secondary amines, LX-H (“HeteroarylAlkyl Amine) and LX (“Phenyl Alkyl Amine”), using procedures disclosedabove. Primary alkylamine XL is first reacted with an aldehydic orketonic carbonyl compound, XI-AH (“Heteroaryl Carbonyl”) and XI-A(“Phenyl Carbonyl”) with azeotropic distillation to form imines, L-H(“Heteroaryl Imine”) and L (“Phenyl Imine”). Said imines L-H and L arethen reduced with or without prior isolation by Reduction Methods 1, 2or 3 as disclosed above and in Schemes 1, 3, and 9 to yield secondaryamines, LX-H (“Heteroaryl Alkyl Amine) and LX (“Phenyl Alkyl Amine”).Said secondary amine LX-H can be converted according to Schemes 31 and32 to Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-alkanols”). Using Schemes 34 and35, LX can be converted to Formula I-C (“Polycyclic Phenyl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-Alkanols”). Compounds of thisinvention in which one aromatic substituent is aryl and the otheraromatic substitutent is heteroaryl can be readily prepared by reactingLX-H with an aryl bromide instead of using an heteroaryl bromide asdescribed in Schemes 31 and 32. Similarly, compounds of this inventionin which one aromatic substituent is aryl and the other aromaticsubstitutent is heteroaryl can be readily prepared by reacting LX withan heteroaryl bromide instead of using an aryl bromide as described inSchemes 34 and 35.

[0334] Particularly useful procedures to prepare Formula I-H (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic PolycyclicAryl and Heteroaryl (R)-Chiral HalogenatedI-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compoundsof the present invention in which the heteroaryl group is directlybonded is disclosed in Schemes 51 to 54. An halogenated, hydroxycontaining primary alkylamine XVL (“Generic Substituted Alkylamine”)formed in Schemes 45 and 48 is itself converted by reaction with LXXI-AH(“Heteroaryl Halide”) to afford secondary amine VLXX-H (“HeteroarylSecondary Amine) using procedures disclosed in Scheme 51 and above.VLXX-H is converted to Formula I-HP (“Generic Polycyclic Aryl andHeteroaryl (R)-Chiral Halogenated I-Substitutedamino-2-propanols”),Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”), and Formula I-CP (“Polycyclic Phenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds byalkylation chemistry with an aralkyl bromide or aralkyloxyalkyl bromideusing either of two procedures disclosed in Scheme 52. Isolation andpurification is effected as disclosed previously. An halogenated,hydroxy containing primary alkylamine XL (“Generic SubstitutedAlkylamine”) formed in Schemes 30 and 33 is itself also converted byreaction with LXXI-AH (“Heteroaryl Halide”) to afford secondary amineLXX-H (“Heteroaryl Secondary Amine) using procedures disclosed in Scheme53 and above. LXX-H is converted to Formula I-H (“Generic PolycyclicAryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-alkanols”) and Formula I-C (“Polycyclic Phenyl(R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”) compounds byalkylation chemistry disclosed in Scheme 54 and previously and as givenabove with reference to Scheme 52. Isolation and purification of I-H andI-C are effected as disclosed previously.

[0335] Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral HalogenatedI-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compoundscan themselves serve as intermediates for conversion to additionalcompounds of this invention. Compounds of Formulas I-H, I-HP, I-C, I-CP,I-HPC and others of the present invention useful as intermediatesinclude those in which the R₇ position substituent in Formulas I-H,I-HP, I-C, I-CP, and I-HPC is a bromo group, hydroxyl group, sulfhydrylgroup, bromomethyl or other bromoalkyl groups, nitro group, amino group,methoxycarbonyl or other alkoxy carbonyl groups, cyano group, or acylgroup. Other preferred compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPCand the present invention useful as intermediates include those in whichthe R₁₀ position substituent is a bromo group, hydroxyl group,sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group,amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyanogroup, or acyl groups. Other compounds of Formulas I-H, I-HP, I-C, I-CP,I-HPC and the present invention useful as intermediates include those inwhich one or more of R₆, R₇ , R₁₁, and R₁₂ substituents in Formula VIIis a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or otherbromoalkyl groups, nitro group, amino group, methoxy carbonyl or otheralkoxy carbonyl groups, cyano group, or acyl groups.

[0336] Scheme 8 discloses the conversion of a 3-bromo substituent at theR₇ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction witha phenol to afford, after isolation and purification as described abovefor Schemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula I-CP (“Polycyclic 3-Phenoxyphenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”).

[0337] Scheme 12 discloses the conversion of a 3-bromo substituent atthe R₇ position in Formula I-HP and I-HPC (“Polycyclic 3-Bromophenyl amd3-Bromoheteroaryl/Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) by reaction with a phenol or thiophenolto afford, after isolation and purification as described above forSchemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula I-HP and I-HPC (“Polycyclic 3-Aryloxyaryl,3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, 3-Aryloxyheteroaryl ,3-Arylthioaryl, 3-Heteroarylthioaryl, 3-Heteroarylthioheteroaryl, and3-Arylthioheteroaryl Aryl amd Heteroaryl/Aryl-Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”).

[0338] Scheme 22 discloses the conversion of a 3-bromo substituent atthe R₇ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction withan aryl borinate or an aryl tin to afford, after isolation andpurification as described above for Schemes 2, 5, 6, 7, and 11,additional compounds of the present invention of Formula I-CP(“Polycyclic 3-Arylphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”).

[0339] Scheme 23 discloses the conversion of a 3-bromo substituent atthe R₇ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction witha primary or secondary amine to afford, after isolation and purificationas described above for Schemes 2, 5, 6, 7, and 11, additional compoundsof the present invention of Formula I-CP (“Polycyclic 3- R₂₂aminophenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

[0340] Scheme 40 discloses the conversion of a 3-bromo substituent atthe R₁₀ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction withan aryl borinate to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula I-CP (“Polycyclic 3-Arylphenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

[0341] Scheme 41 discloses the conversion of a 3-bromo substituent atthe R₁₀ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction witha heteroaryl dibutyl tin compound to afford, after isolation andpurification as described above for Schemes 2, 5, 6, 7, and 11,additional compounds of the present invention of Formula I-CP(“Polycyclic 3-Heteroarylphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”).

[0342] Scheme 21 discloses the conversion of a 3-bromomethyl substituentat the R₇ position in Formula I-CP (“Polycyclic 3-Bromomethylphenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) by reaction withan aryl borinate to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula I-CP (“Polycyclic 3-Arylmethylphenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

[0343] Scheme 13 discloses the conversion of a 3-hydroxyl substituent atthe R₇ position in Formula I-HP and I-HPC (“Polycyclic 3-Hydroxyphenylamd 3-Hydroxyheteroaryl/Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) by reaction with an aryl bromide orheteroaryl bromide to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula I-HP and I-HPC (“Polycyclic3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and3-Aryloxyheteroaryl Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”).

[0344] Scheme 14 discloses the conversion of a 3-hydroxyl substituent atthe R₇ position in Formula I-CP (“Polycyclic 3-Hyroxyphenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction withan aryl bromide to afford, after isolation and purification as describedabove for Schemes 2, 5, 6, 7, and 11, additional compounds of thepresent invention of Formula I-CP (“Polycyclic 3-Phenoxyphenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

[0345] Scheme 15 discloses the conversion of a 3-hydroxyl substituent atthe R₇ position in Formula I-HP and I-HPC (“Polycyclic 3-Hydroxyphenylamd 3-Hydroxyheteroaryl/Aryl-Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds by reaction with an aralkylbromide or heteroaralkyl bromide to afford, after isolation andpurification as described above for Schemes 2, 5, 6, 7, and 11,additional compounds of the present invention of Formula I-HP and I-HPC(“Polycyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl,3-Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Aryl-Heteroaryl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

[0346] Scheme 16 discloses the conversion of a 3-hydroxyl substituent atthe R₇ position in Formula I-CP (“Polycyclic 3-Hyroxyphenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction withan aralkyl bromide to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula I-CP (“Polycyclic 3-Aralkyloxyaryl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

[0347] Scheme 20 discloses the conversion of a 3-hydroxyl substituent atthe R₇ position in Formula I-CP (“Polycyclic 3-Hyroxyphenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction withan R₁₇-bromide to afford, after isolation and purification as describedabove for Schemes 2, 5, 6, 7, and 11, additional compounds of thepresent invention of Formula I-CP (“Polycyclic 3- R₁₇-oxyaryl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”).

[0348] Scheme 19 discloses the conversion of a 3-thio substituent at theR₇ position in Formula I-CP (“Polycyclic 3-thiophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction withan R₁₇-bromide to afford, after isolation and purification as describedabove for Schemes 2, 5, 6, 7, and 11, additional compounds of thepresent invention of Formula I-CP (“Polycyclic 3- R,₇thiaaryl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”). “Polycyclic 3- R₁₇thiaaryl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols” can be oxidizedto sulfonyl compounds of Formula I-CP (“Polycyclic 3-R₁₇sulfonylphenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

[0349] Scheme 24 discloses the conversion of a 3-nitro substituent atthe R₇ position in Formula I-CP (“Polycyclic 3-Nitrophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by hydrogenationto afford, after isolation and purification as described above forSchemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula ICP (“Polycyclic 3-Aminophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”). “Polycyclic 3-Aminophenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols” can be acylatedto acyl amide compounds of Formula I-CP (“Polycyclic3-R₁₇-C(O)amidophenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”).

[0350] Schemes 25 and 26 disclose the conversion of a 3-aminosubstituent at the R₇ position in Formula I-CP (“Polycyclic3-Aminophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”)compounds by reaction with carbonyl compounds to afford, after isolationand purification as described above for Schemes 2, 5, 6, 7, and 11,additional compounds of the present invention of Formula I-CP(“Polycyclic 3-(Saturated Nitrogen Heterocycl-1yl)aryl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols” and (“Polycyclic3-(Unsaturated Nitrogen Heterocycl-1yl)aryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”, respectively).

[0351] Scheme 27 discloses the conversion of a 3-methoxycarbonylsubstituent at the R₇ position in Formula I-CP (“Polycyclic3-Carbomethoxyphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds by reaction with aminationreagents to afford, after isolation and purification as described abovefor Schemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula I-CP (“Polycyclic 3-Carboxamidophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”).

[0352] Scheme 28 discloses the conversion of a 3-cyano substituent atthe R₇ position in Formula I-CP (“Polycyclic 3-Cyanophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”) compounds by reaction withorganometallic reagents to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula I-CP (“Polycyclic 3-Acylphenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”). Said“Polycyclic 3-Acylphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”, according to Scheme 29 can be reducedto hydroxyl compounds of Formula I-CP (“Polycyclic3-hydroxysubstitutedmethylphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”).

[0353] Scheme 36 discloses the conversion of a 3-methoxycarbonylsubstituent at the R₁₀ position in Formula I-CP (“Polycyclic3-Carbomethoxyphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds by reaction with aminationreagents to afford, after isolation and purification as described abovefor Schemes 2, 5, 6, 7, and 11, additional compounds of the presentinvention of Formula I-CP “Polycyclic 3-Carboxamdophenyl (R)-ChiralHalogenated 1-Substitutedamino-2-Propanols”).

[0354] Scheme 37 discloses the conversion of a 3-methoxycarbonylsubstituent at the R₁₀ position in Formula I-CP (“Polycyclic3-Carbomethoxyphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds by reaction with anorganometallic reagent to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula I-CP “Polycyclic3-(bis-R₂₀-hydroxymethyl)aryl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”).

[0355] Scheme 38 discloses the conversion of a 3-methoxycarbonylsubstituent at the R₁₀ position in Formula I-CP (“Polycyclic3-Carbomethoxyphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds by reaction with lithiumaluminum hydride to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6, 7, and 11, additional compounds ofthe present invention of Formula I-CP (“Polycyclic 3-Hydroxymethylphenyl(R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

[0356] Scheme 39 discloses the conversion of a 3-methoxycarbonylsubstituent at the R₁₀ position in Formula I-CP (“Polycyclic3-Carbomethoxyphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds by reaction with analkylation reagent to afford, after isolation and purification asdescribed above for Schemes 2, 5, 6,7, and 11, additional compounds ofthe present invention of Formula I-CP (“Polycyclic3-(bis-R₂₁-hydroxymethyl)phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”).

[0357] Scheme 55 discloses the conversion of a 3-methoxycarbonylsubstituent at the R₁₀ position in Formula I-CP (“Polycyclic3-Carbomethoxyphenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”) compounds by reaction intially with anamidation reagent and then an R₂₀-organometallic reagent to afford,after isolation and purification as described above for Schemes 2, 5, 6,7, and 11, additional compounds of the present invention of Formula I-CP(“Polycyclic 3-( R₂₀-carbonyl)phenyl (R)-Chiral Halogenated1-Substitutedamino-2-Propanols”).

[0358] Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) and othercompounds of this invention posssessing hydroxyl, thiol, and aminefunctional groups can be converted to a wide variety derivatives. Thehydroxyl group, wherein R₁₆ is a hydrogen and X is oxy, of compounds ofFormulas I-H, I-HP, I-HPC, I-C, and I-CP can be readily converted toesters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoricacids. Acylation to form a carboxylic acid ester is readily effectedusing a suitable acylating reagent such as an aliphatic acid anhydrideor acid chloride. The corresponding aryl and heteroaryl acid anhydridesand acid chlorides can also be used. Such reactions are generallycarried out using an amine catalyst such as pyridine in an inertsolvent. In like manner, compounds of Formulas I-H, I-HP, I-C, I-CP,I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least onehydroxyl group present in the form of an alcohol or phenol can beacylated to its corresponding esters. Similarly, carbamic acid esters(urethans) can be obtained by reacting any hydroxyl group withisocyanates and carbamoyl chlorides. Sulfonate, phosphonate, andphosphate esters can be prepared using the corresponding acid chlorideand similar reagents. Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC,Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least one thiol grouppresent can be converted to the corresponding thioesters derivativesanalogous to those of alcohols and phenols using the same reagents andcomparable reaction conditions. Compounds of Formulas I-H, I-HP, I-C,I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least oneprimary or secondary amine group present can be converted to thecorresponding amide derivatives. Amides of carboxylic acids can beprepared using the appropriate acid chloride or anhydrides with reactionconditions analogous to those used with alcohols and phenols. Ureas ofthe corresponding primary or secondary amine can be prepared usingisocyanates directly and carbamoyl chlorides in the presence of an acidscavenger such as triethylamine or pyridine. Sulfonamides can beprepared from the corresponding sulfonyl chloride in the presence ofaqueous sodium hydroxide. Suitable procedures and methods for preparingthese derivatives can be found in House's Modern Synthetic Reactions, W.A. Benjamin, Inc., Shriner, Fuson, and Curtin in The SystematicIndentification of Organic Compounds, 5th Edition, John Wiley & Sons,and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, JohnWiley & Sons. Reagents of a wide variety that can be used to derivatizehydroxyl, thiol, and amines of compounds of Formulas I-H, I-HP, I-C,I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP are available fromcommercial sources or the references cited above, which are incorporatedherein by reference.

[0359] Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) and othercompounds of this invention posssessing hydroxyl, thiol, and aminefunctional groups can be alkylated to a wide variety derivatives. Thehydroxyl group, wherein R₁₆ is a hydrogen and X is oxy, of compounds ofFormulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and CycloI-CP can be readily converted to ethers. Alkylation to form an ether isreadily effected using a suitable alkylating reagent such as an alkylbromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl,heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkylbromides, iodides, and sulfonates can also be used. Such reactions aregenerally carried out using an alkoxide forming reagent such as sodiumhydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyllithium using an inert polar solvent such as DMF, DMSO, THF, andsimilar, comparable solvents. In like manner, compounds of Formulas I-H,I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that haveat least one hydroxyl group present in the form of an alcohol or phenolcan be alkylated to their corresponding ethers. Compounds of FormulasI-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP thathave at least one thiol group present can be converted to thecorresponding thioether derivatives analogous to those of alcohols andphenols using the same reagents and comparable reaction conditions.Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C,and Cyclo I-CP that have at least one primary, secondary or tertiaryamine group present can be converted to the corresponding quaternaryammonium derivatives. Quaternary ammonium derivatives can be preparedusing the appropriate bromides, iodides, and sulfonates analogous tothose used with alcohols and phenols. Conditions involve reaction of theamine by warming it with the alkylating reagent with a stoichiometricamount of the amine (i.e., one equivalent with a tertiary amine, twowith a secondary, and three with a primary). With primary and secondaryamines, two and one equivalents, respectively, of an acid scavenger areused concurrently. Tertiary amines can be prepared from thecorresponding primary or secondary amine by reductive alkylation withaldehydes and ketones using reduction methods 1, 2, or 3 as shown inScheme 3. Suitable procedures and methods for preparing thesederivatives can be found in House's Modem Synthetic Reactions, W. A.Benjamin, Inc., Shriner, Fuson, and Curtin in The SystematicIndentification of Organic Compounds, 5th Edition, John Wiley & Sons,and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, JohnWiley & Sons. Perfluoroalkyl derivatives can be prepared as described byDesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of awide variety that can be used to derivative hydroxyl, thiol, and aminesof compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, CycloI-C, and Cyclo I-CP are available from commercial sources or thereferences cited above, which are incorporated herein by reference.

[0360] Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-ChiralHalogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“GenericPolycyclic Aryl and Heteroaryl (R)-Chiral Halogenated1-Substitutedamino-2-propanols”), Formula I-HPC (“PolycyclicAryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”),Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“PolycyclicPhenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) andcertain other compounds of this invention can be converted, according toSchemes 17 and 18, to the corresponding cyclic derivatives representedby “Tricyclic tertiary-oxyalkylamines” and exemplified by Formulas CycloI-H (“Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated(N+1)-Cycloazaalkoxy”), Cyclo I-C (“Polycyclic Aryl Phenyl (R)-ChiralHalogenated (N+1)-Cycloazaalkoxy”) and Cyclo I-CP (“Polycyclic PhenylPhenyl (R)-Chiral Halogenated Cycloazaalkoxy”). The hydroxyl group,wherein R₁₆ is a hydrogen and X is oxy, of compounds of Formulas I-H,I-HP, I-C, I-CP, and I-HPC can be cyclized to corresponding cyclicethers. Compounds suitable for cyclization will normally have at leastone leaving group within 5 to 10 continuous atoms of the hydroxyl groupwherein R₁₆ is a hydrogen and X is oxy. Most preferrably the leavinggroup will be within 5 to 7 atoms of the hydroxyl group so as to form a6 to 8 membered ring heteroatom containing ring. When the leaving groupis part of an aromatic ring system, the leaving group will bepreferrably in an ortho position. Suitable leaving groups generallyinclude halides, sulfates, sulfonates, trisubsituted amino,disubstituted sulfonium, diazonium, and like, and, in the case ofaromatic systems, also includes nitro, alkoxy, aryloxy, heteroaryloxy,and alkylthio.

[0361] The cyclization reaction to form “Tricyclictertiary-oxyalkylamines” of Formulas Cyclo I-H, Cyclo I-C and Cyclo I-CPcan be accomplished by aromatic and aliphatic nucleophilic substitutionreactions such as those disclosed in March's Advanced Organic Chemistry,4th Edition, John Wiley & Sons, especially at pages 293-412 and 649-658and the references cited therein, which are incorporated herein byreference. Hydroxyl containing suitably substituted compounds can beconverted to a cyclic analog by heating a suitably substituted compoundunder anhydrous conditions in a suitable solvent, such asdimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetraglyme,or hexamethylphosphoramide, in the presence of a suitable base such aspotassium carbonate, cesium carbonate, sodium hydroxide, potassiumtertiary-butoxide, or lithium diisopropylamide. Alternately, sodiumamide in anhydrous ammonia solvent can be used. Temperatures in therange of −20 ° C. to 200 ° C. can be used for time periods of 30 minutesto more than 24 hours. The preferred temperature can be selected bystandard synthetic chemical technique balancing maximum yield, maximumpurity, cost, ease of isolation and operation, and time required.Isolation of the “Tricyclic tertiary-oxyalkylamines” can be effected asdescribed above for other tertiary-oxyalkylamines. Representative“Tricyclic tertiary-oxyalkylamines” prepared using the methodologydescribed above are included in Table 8.

[0362] The following examples are provided to illustrate the presentinvention and are not intended to limit the scope thereof. Those skilledin the art will readily understand that known variations of theconditions and processes of the following preparative procedures can beused to prepare these compounds. TABLE 8 Structure of SubstitutedTricyclictertiary-2-oxyalkylamines.

Y Z R₅ K₁-R₆ R₁₀ K₂-R₁₁ R₁₂ R₁₃ CH₂ — 4-chloro-3-ethylphenoxy C—H HC—CF₃ H H CH₂ — 4-chloro-3-ethylphenoxy N H C—CF₃ H H CH₂ —4-chloro-3-ethylphenoxy C—H H C—H CF₃ H CH₂ — 4-chloro-3-ethylphenoxy NH C—H CF₃ H CH₂ — 4-chloro-3-ethylphenoxy C—H H N CF₃ H — —4-chloro-3-ethylphenoxy C—H H C—CF₃ H H — — 4-chloro-3-ethylphenoxy N HC—CF₃ H H — — 4-chloro-3-ethylphenoxy C—H H C—H CF₃ H — —4-chloro-3-ethylphenoxy N H C—H CF₃ H — — 4-chloro-3-ethylphenoxy C—H HN CF₃ H

Y Z R₇ K₁—R₆ R₁₀ K₂—R₁₁ R₅ R₈ CH₂ — 4-chloro-3-ethylphenoxy C—H OCF₂CF₂HC—H H H CH₂ — 4-chloro-3-ethylphenoxy N OCF₂CF₂H C—H H H CH₂ —4-chloro-3-ethylphenoxy C—H OCF₂CF₂H N H H CH₂ — phenoxy C—H OCF₂CF₂HC—H H H CH₂ — phenoxy N OCF₂CF₂H C—H H H CH₂ — phenoxy C—H OCF₂CF₂H N HH CH₂ — 4-chloro-3-ethylphenoxy C—H CF₂CF₃ C—H H H CH₂ —4-chloro-3-ethylphenoxy N CF₂CF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxyC—H CF₂CF₃ N H H CH₂ — phenoxy C—H CF₂CF₃ C—H H H CH₂ — phenoxy N CF₂CF₃C—H H H CH₂ — phenoxy C—H CF₂CF₃ N H H CH₂ — 4-chloro-3-ethylphenoxy C—HCF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy N CF₃ C—H H H CH₂ —4-chloro-3-ethylphenoxy C—H CF₃ N H H CH₂ — phenoxy C—H CF₃ C—H H H CH₂— phenoxy N CF₃ C—H H H CH₂ — phenoxy C—H CF₃ N H H CH₂ —4-chloro-3-ethylphenoxy C—H OCF₂CF₂H C—H H F CH₂ —4-chloro-3-ethylphenoxy N OCF₂CF₂H C—H H F CH₂ — 4-chloro-3-ethylphenoxyC—H OCF₂CF₂H N H F CH₂ — 4-chloro-3-ethylphenoxy C—H 2-furyl C—H H H CH₂— 4-chloro-3-ethylphenoxy N 2-furyl C—H H H CH₂ —4-chloro-3-ethylphenoxy C—H 2-furyl N H H CH₂ — 4-chloro-3-ethylphenoxyC—H SCF₃ C—H H H CH₂ — 4-chloro-3-ethylphenoxy N SCF₃ C—H H H CH₂ —4-chloro-3- C—H SCF₃ N H H ethylphenoxy

[0363]

[0364] The following examples are provided to illustrate the presentinvention and are not intended to limit the scope thereof. Withoutfurther elaboration, it is believed that one skilled in the art can,using the preceding descriptions, utilize the present invention to itsfullest extent. Therefore the following preferred specific embodimentsare to be construed as merely illustrative and not limitative of theremainder of the disclosure in any way whatsoever. Compounds containingmultiple variations of the structural modifications illustrated in thepreceding schemes or the following Examples are also contemplated. Thoseskilled in the art will readily understand that known variations of theconditions and processes of the following preparative procedures can beused to prepare these compounds.

[0365] One skilled in the art may use these generic methods to preparethe following specific examples, which have been or may be properlycharacterized by ¹H NMR and mass spectrometry. These compounds also maybe formed in vivo.

[0366] The following examples contain detailed descriptions of themethods of preparation of compounds of Formula V-H. These detaileddescriptions fall within the scope and are presented for illustrativepurposes only and are not intended as a restriction on the scope of theinvention. All parts are by weight and temperatures are Degreescentigrade unless otherwise indicated.

EXAMPLE 1

[0367]

(2R,S)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

[0368] EX-1A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL ofcarbon tetrachloride under nitrogen was added2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixturewas refluxed for 2 h, then cooled to room temperature and quenched with300 mL of water. The organic layer was collected, washed with water andbrine, dried over MgSO₄, and concentrated in vacuo to give 66.0 g (96%)of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzeneproduct as a yellow oil. ¹H NMR indicates that this oil is a mixture ofproducts: 7% dibrominated, 67% monobrominated, and 20% startingmaterial. The crude product was used without further purification. ESMSm/z=287 [M+H]⁺.

[0369] EX-1B) The crude product (56 g, 0.14 mol) from EX-1A in 200 mL ofcyclohexane was added dropwise under nitrogen to a solution of3-phenoxyaniline (89 g, 0.480 mol) in 500 mL of cyclohexane. Thereaction mixture was refluxed overnight, then cooled to room temperatureand diluted with water and diethyl ether. The layers were separated, andthe aqueous layer was extracted with diethyl ether. The combined organiclayers were dried over MgSO₄ and concentrated in vacuo to give a darkoil. The crude product was purified by column chromatography on silicagel eluting with 1:4 ethyl acetate in hexane to afford 44.96 g (83%) ofthe desiredN-(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amineproduct as a yellow oil. ESMS m/z=392 [M+H]⁺.

[0370] To a mixture of the amine product (15.0 g, 0.038 mol) from EX-1Band 1,1,1-tri-fluoro-2,3-epoxypropane (8.58 g, 0.077 mol, TCI) was addeda suspension of ytterbium (III) trifluoromethanesulfonate (2.37 g,0.0031 mol) in 15 mL of acetonitrile. The resulting mixture was heatedat 50° C. in a sealed glass vial for 1.5 h. The reaction mixture wascooled to room temperature then diluted with water and ethyl acetate andextracted. The organic layers were combined, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel eluting with 1:4 ethyl acetate in hexane toafford 12.03 g (62%) of the desired(2RS)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil.Anal. calcd. for C₂₄H₂₀F₇NO₃: C, 57.26; H, 4.00; N, 2.78. Found: C,56.96; H, 4.35; N, 2.69. HRMS calcd. 504.1410 [M+H]⁺, found: 504.1431.¹H NMR (CDCl₃) δ7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H),6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H),4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H).¹⁹F NMR (CDCl₃) δ−79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).

EXAMPLE 2

[0371]

(2R)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0372] On a Chiralpak AD HPLC column,(2RS)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(12.2 g, 0.024 mol) from EX-1 was purified by chiral chromatography togive 1.4 g (0.003 mol, 12%) of(2R)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol as a light yellow oil. Chiralpurification was accomplished by eluting with 1:9 isopropanol in heptaneat 1.0 mL/min with 250 nm UV detection. The product eluted at 8.43 min.[α]₅₈₉=+16.8.0 (c 0.125 g/dL, CH₃CN), [α]₃₆₅=+84.0 (c 0.125, CH₃CN).Anal. calcd. for C₂₄H₂₀F₇NO₃: C, 57.26; H, 4.00; N, 2.78. Found: C,56.96; H, 4.35; N, 2.69. HRMS calcd.: 504.1410 [M+H]⁺, found: 504.1388.¹H NMR (CDCl₃) δ7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H),6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H),4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H).¹⁹F NMR (CDCl₃) δ−79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).

EXAMPLE 3

[0373]

(2S)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0374] On a Chiralpak AD HPLC column,(2RS)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(12.2 g, 0.024 mol) from EX-1 was purified by chiral chromatography togive 10.5 g (0.021 mol, 86%) of(2S)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-l,1,1-trifluoro-2-propanol as a light yellow oil. Chiralpurification was accomplished by eluting with 1:9 isopropanol in heptaneat 1.0 mL/min with 250 nm UV detection. The product eluted at 6.36 min.[α]₅₈₉=−17.0 (c 0.265 g/dL, CH₃CN), [α]₃₆₅=−85.7 (c 0.265, CH₃CN). Anal.calcd. For C₂₄H₂₀F₇NO₃: C, 57.26; H, 4.00; N, 2.78. Found: C, 56.96; H,4.35; N, 2.69. HRMS calcd.: 504.1410 [M+H]⁺, found: 504.1431. ¹H NMR(CDCl₃) δ7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94(d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60(t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR(CDCl₃) δ−79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).

EXAMPLE 4

[0375]

(2R)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0376] Using a procedure adopted from H. C. Brown et al. (J. Org Chem.60, 41-46, (1995)), R-(+)-1,1,1-trifluoro-2,3-epoxypropane was preparedbeginning with the transfer of (+)-B-chlorodiisopinocampheylborane((+)-DIP-Cl, 1.2 kg, 3.74 mol) to a 5 L three neck flask containing 5 Lof ether under nitrogen. Anhydrous ether (5 L) was added, and themixture was stirred until the solids dissolved and the temperatureequilibrated to 0° C. Then 3-bromotrifluoroacetone (326 mL, 3.14 mol)was added, and the reaction was stirred for 72 h while maintaining thetemperature between −4 and +5° C. The reaction was followed by ¹⁹F NMRby removing an aliquot (20 μL), quenching with anhydrous methanol (0.6mL), and referencing to external D₂O. The reduction was 68% completeafter 48 h. The ether was removed under vacuum (100 torr to 0.1 torr),leaving a pale, viscous oil. A 5 L 3-neck flask equipped with stirrer,dropping funnel, and short-path distillation head with chilled receiverwas charged with 50% (w/w) aqueous NaOH and heated to 40° C. Withexternal heat removed, the quenched reduction mixture was added dropwiseto the aqueous NaOH, with the rate controlled to maintain the pottemperature below 65° C. The product epoxide formed immediately,distilling over with a head temperature of 32-42° C. A yellow-orangesolid byproduct was broken up by stirring and some foaming was observed.When the distillation was complete, 145 g (43%) of the desiredR-(+)-1,1,1-trifluoro-2,3-epoxy-propane product was obtained as a clear,colorless oil. ¹H NMR (C₆D₆) δ2.50 (m, 1H, CF₃CH), 2.15 (dd, 1H, J=2.10,5.01 Hz), 1.75 (m, 1H). ¹⁹F NMR (C₆D₆) δ−75.4 (d, J=4.7 Hz). ChiralGC/MS analysis was performed on the corresponding diethylamine adductusing a gamma cyclodextrin column (Supelco gammadex120G-cyclodextrinfused silica): 4 drops of the epoxide,R-(+)-1,1,1-trifluoro-2,3-epoxypropane, and 4 drops of diethylamine wereheated briefly in a sealed vial, cooled, diluted with methyl t-butylether, and analyzed. Found: two gc peaks: 10.97 min and 11.11 min (ratio1:230; 99% ee), where the R-product predominated. MS calcd. forC₇H₁₄F₃NO: m/z=186 [M+H]⁺, found: 186, for both gc peaks. In contrast,the diethylamine adduct obtained with the TCI trifluoromethyl-oxirane(lot OGH01) from EX-1, gave 2 peaks with identical MS signals m/z=186,10.96 min and 11.12 min (ratio 8.5:1; 79% ee), where the S-productpredominated.

[0377] To a mixtureN-(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl] methyl]-aminefrom EX-1B (1.48 g, 0.0038 mol) andR-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.64 g, 0.0057 mol) was added asuspension of ytterbium (III) trifluoro-methanesulfonate (0.23 g, 0.0004mol) in 1.5 mL of acetonitrile. The resulting mixture was heated at 50°C. in a sealed glass tube for 1.5 h. The reaction mixture was cooled toroom temperature then diluted with water and ethyl acetate andextracted. The organic layers were combined, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel eluting with 1:4 ethyl acetate in hexane toafford 1.2 g (63%) of the desired(2R)-3-[(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a pure yellow oil (>96% ee by chiral HPLC analysis), whichwas identical in all respects to EX-2. Anal. calcd. for C₂₄H₂₀F₇NO₃: C,57.26; H, 4.00; N, 2.78. found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd.:504.1410 [M+H]⁺, found: 504.1431. ¹H NMR (CDCl₃) δ7.28 (m, 4H), 7.14 (t,1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd,1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d,1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ−79.0 (s, 3F), −88.21(d, 2F), −137.05 (dd, 2F).

[0378] Additional examples can be prepared by one skilled in the artusing similiar methods and commercially available epoxides. For example,3-[(3-phenoxyphenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1-chloro-2-propanolscan be prepared from the reaction ofN-(3-phenoxyphenyl)-[[3-(trifluoromethoxy)phenyl]methyl]amine witheither (R)-epichlorohydrin or (S)-epichlorohydrin, as illustrated inExample Table 1.

Example Table 1.3-[(3-phenoxyphenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1-chloro-2-propanols.

[0379]

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H]⁺ [M +H]⁺ 5 OH H 452.1240 452.1245 6 H OH 452.1240 452.1259

EXAMPLE 7

[0380]

(2R)-3-[(3,4,5-trimethoxyphenyl)[[13-(trifluoromethylthio)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol

[0381] EX45A) To a 1,2-dichloroethane (12 mL) solution of3,4,5-trimethoxyaniline (0.80 g, 4.4 mmol) was added(3-trifluoromethylthio)benzaldehyde (0.90 g, 4.4 mmol), NaB(OAc)₃H (1.20g, 5.66 mmol) and acetic acid (0.26 ML, 4.5 mmol). The cloudy solutionwas stirred at room temperature for 1 h. The reaction mixture was pouredinto water and extracted with dichloromethane. The organic layer waswashed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated togive 1.58 g (96%) of the desiredN-(3,4,5-trimethoxyphenyl)[[3-trifluoromethylthiophenyl]methyl]amineproduct as an off-white solid. MS: m/z=373.8 [M+H]⁺.

[0382] To an acetonitrile (3.2 mL) solution of amine (1.20 g, 3.2 mmol)from EX45A was added R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.55 mL,6.4 mmol) from EX-4 and Yb(OTf)₃ (0.40 g, 0.64 mmol). The cloudysolution was stirred in a sealed flask at 50° C. for 18 h. The cooledreaction mixture was diluted with diethyl ether and washed with waterand brine. The organic layer was dried (MgSO₄) and evaporated to an oil.Purification by flash column chromatography on silica gel eluting with20% ethyl acetate in hexane gave an oil which was triturated withhexanes to give a white solid. The precipitate was isolated byfiltration and dried in vacuo to give 0.82 g (53%) of the desired(2R)-3-[(3,4,5-trimethoxyphenyl)[[3-(trifluoromethylthio)phenyl]methyl]-amino]-1,1,1,-trifluoro-2-propanol product as a white solid,m.p. 88.9-89.1° C. (95% ee by chiral HPLC). Anal. calcd. forC₂₀H₂₁NO₄SF₆: C, 49.48; H, 4.36; N, 2.89. Found: C, 49.29; H4.21; N,2.81. HRMS calcd.: 486.1174 [M+H]⁺, found: 486.1158. ¹H NMR (C₆D₆) δ3.10(d, 1H), 3.18 (dd, 1H), 3.32 (s, 6H), 3.53 (d, 1H), 3.64 (s, 3H), 4.01(m, 1H), 4.21 (dd, 2H), 5.70 (s, 2H), 6.80 (t, 1H), 6.94 (d, 1H), 7.23(d, 1H), 7.37 (s, 1H). [α]₅₈₉=+26.8 (c 1.099 g/dL, CHCl₃).

EXAMPLE 8

[0383]

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0384] EX8A) To a solution of 1,3-dinitrobenzene (16.8 g, 0.1 mol) and4-chloro-3-ethylphenol (15.6 g, 0.1 mol) in 200 mL of dimethylsulfoxidewas added cesium carbonate (65 g, 0.2 mol). The reaction mixture washeated at 100° C. under nitrogen overnight then cooled to roomtemperature. The reaction mixture was filtered through celite thenrinsed with diethyl ether and a small amount of water. The filtrate wasextracted several times with diethyl ether. The organic layers werecombined, washed with water and brine, dried over MgSO₄, andconcentrated in vacuo to give 21.8 g (78%) of the desired3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene product as a dark orange oil,which was greater than 90% pure by reverse phase HPLC analysis. HRMScalcd. for C₁₄H₁₂ClNO₃:295.0849 [M+NH₄]⁺, found 295.0862.

[0385] EX-8B) To a solution of3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (10 g, 0.036 mol) from EX8Ain 400 mL of glacial acetic acid and 1 mL of water was added zinc metal(20 g, 0.305 mol) at room temperature, and the resultant mixture wasstirred for 1 h. The reaction mixture was filtered through celite. Thefiltrate was neutralized with ammonium hydroxide and extracted withdiethyl ether. The organic layer was washed with water and brine, driedover MgSO₄, and concentrated in vacuo to give 10 g (100%) of the desired3-(4-chloro-3-ethylphenoxy)aniline product as a dark orange oil, whichwas greater than 90% pure by reverse phase HPLC analysis. HRMS calcd.for C₁₄H₁₄ClNO: 248.0842 [M+H]⁺, found: 248.0833.

[0386] EX8C) To a solution of 3-(4-chloro-3-ethylphenoxy)aniline (2.0 g,8.1 mmol) from EX8B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.6g, 7.3 mmol) in 30 mL of dichloroethane was added sodiumtriacetoxyborohydride (2.0 g, 9.7 mmol) and glacial acetic acid (0.51mL, 8.9 mmol). The reaction mixture was stirred at room temperature for1 h then quenched with water and extracted with diethyl ether. Theorganic layer was washed with water and brine, dried over MgSO₄, andconcentrated in vacuo to give 3.5 g (95%) of the desiredN-[(4-chloro-3-ethylphenoxy)phenyl]-3-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amineproduct as a brown oil, which was greater than 90% pure by reverse phaseHPLC analysis. HRMS calcd. for C₂₃H₂₀ClF₄NO₂: 454.1197 [M+H]⁺, found:454.1220.

[0387] A solution ofN-[(4-chloro-3-ethylphenoxy)phenyl]-3-[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amine(1.8 g, 4.0 mmol) from EX8C, R-(+)-1,1,1-trifluoro-2,3-epoxy-propane(0.64 g, 0.0057 mol) from EX-4, and ytterbium (III)trifluoromethanesulfonate (0.25 g, 0.4 mmol) in 1.5 mL of acetonitrilewas heated at 40° C. in a sealed glass tube for 1 h. The reactionmixture was cooled to room temperature then diluted with water anddiethyl ether and extracted. The ether layer was washed with water andbrine, dried over MgSO₄, and concentrated in vacuo The crude product waspurified by column chromatography on silica gel eluting with 1:7:0.01 ofethyl acetate:hexane:ammonium hydroxide to afford 1.5 g (66%) of thedesired(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-tri-fluoro-2-propanolproduct as a yellow oil (96% ee by chiral HPLC analysis). [α]₅₈₉=+36.9(c 1.044 g %, CHCl₃), [α]365²⁵=+189.7 (c 1.044 g %, CHCl₃). Therefractive index @ 25° C. is 1.5275. Anal. calcd. for C₂₆H₂₃ClF₇NO₃: C,55.18; H, 4.10; N, 2.48. found: C, 54.92; H, 4.05; N, 2.33. HRMS calcd.:566.1330 [M+H]⁺, found: 566.1323. H NMR (CDCl₃) δ7.30 (t, 1H), 7.20 (d,1H), 7.15 (t, 1H), 7.08 (t, 2H), 7.00 (s, 1H), 6.86 (d, 1H), 6.68 (dd,1H), 6.48 (dd, 1H), 6.36 (dd, 1H), 6.34 (t, 111), 5.81 (t, 1H), 4.62 (s,2H), 4.32 (m, 1H), 3.84 (dd, 1H), 3.55 (dd, 1H), 2.67 (q, 2H), 2.45 (bs,1H), 1.17 (t, 3H). ¹⁹F NMR (CDCl₃) δ−79.22 (d, 3F), −88.57 (m, 2F),-137.16 (dt, 2F).

[0388] Additional examples of(2R)-3-[[3-(substituted-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolsand(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-substituted-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanolscan be prepared by one skilled in the art using similar methods, asshown in Example Tables 2 and 3, respectively.

Example Table 2.(2R)-3-[[3-(Substituted-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

[0389]

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 94-methyl 518.1566 518.1587 10 3-isopropyl 546.1879 546.1900 11 3-ethyl532.1723 532.1713

Example Table 3.(2R)-3-[[3-(4-Chloro-3-ethylphenoxy)phenyl][[3-substituted-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

[0390]

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 123-trifluoromethoxy 534.1271 534.1309 13 3-trifluoromethyl, 4-fluoro536.1228 536.1265 14 2-fluoro, 4-trifluoromethyl 536.1228 536.1241 152-trifluoromethyl, 4-fluoro 536.1228 536.1245 16 2-fluoro,5-trifluoromethyl 536.1228 536.1252 17 2-fluoro, 6-trifluoromethyl536.1228 536.1199

EXAMPLE 18

[0391]

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,1,2,2-pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0392] EX-18A) Sodium pentafluoroethyl propionate (8.4 g, 50 mmol) and3-iodotoluene (5.5 g, 25 mmol) were dissolved in anhydrous DMF (300 mL)under nitrogen. CuI (9.5 g, 50 mmol) was added, and the mixture washeated to 160° C. under nitrogen for 4 h, at which time a 15 mL fractionof a mixture of DMF and 3-pentafluoroethyl toluene was collected. Thedistillate was diluted with Et₂O and was washed with brine. The etherlayer was dried over MgSO₄, filtered and concentrated in vacuo to give5.25 g (55%) of the desired 3-pentafluoroethyl-toluene product as acolorless oil. ¹H NMR (CDCl₃) δ7.36 (m, 4H), 2.40 (s, 3H). ¹⁹F NMR(CDCl₃) δ−85.2 (s, 3F), −115.2 (s, 2F).

[0393] EX-18B) The 3-pentafluoroethyl-toluene (2.9 g, 13.8 mmol) productfrom EX-18A and N-bromosuccinimide (2.5 g, 13.8 mmol) were dissolved inCCl₄ (25 mL). AIBN (50 mg, 0.3 mmol) was added, and the mixture wasrefluxed for 3.5 h under N₂. The reaction mixture was cooled to roomtemperature and diluted with water. The layers were separated, and theorganic layer was washed with brine, dried with anhydrous MgSO₄,filtered, and concentrated in vacuo to give 3.4 g (87%) of a colorlessoil. The ¹H NMR spectrum indicated that the crude product contained3-pentafluoroethyl-benzylbromide (70%), the benzyldibromide (10%) andpentafluoroethyl toluene (20%). ¹H NMR (CDCl₃) δ7.60 (m, 2H), 7.50 (m,2H), 4.50 (s, 2H). ¹⁹F NMR (CDCl₃) δ−85.1 (s, 3F), −115.4 (s, 2F).

[0394] EX-18C) A solution of 3-(4-chloro-3-ethylphenoxy)aniline (1.7 g,6.9 mmol) was prepared in cyclohexane (13 mL). A solution of crude3-pentafluoroethyl benzylbromide (1 g, 3.5 mmol) product from EX-18B incyclohexane (10 mL) was added dropwise under nitrogen over 3 min. Thereaction mixture was refluxed under N₂ for 24 h and then was cooled toroom temperature. The mixture was diluted with Et₂O and saturatedaqueous NaHCO₃. The layers were separated, and the aqueous layer wasextracted with Et₂O. The organic layer was washed with brine, dried withanhydrous MgSO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography on silica get eluting with hexanes in ethylacetate (95:5) which gave 0.56 g (35%) of the desiredN-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoro-ethyl)phenyl]-methyl]amineproduct as a brown oil. ¹H NMR (CDCl₃) δ7.53 (m, 4H), 7.27 (d, 1H), 7.15(t, 1H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.41 (tt, 2H), 6.30 (t, 1H), 4.41(s, 2H), 2.73 (q, 2H), 1.23 (t, 3H). ¹³C NMR (CDCl₃) δ158.6, 156.1,143.4, 141.3, 140.2, 131.3, 130.7, 130.4, 129.4, 128.1, 120.4, 117.8,108.8. 103.9, 48.5, 27.5, 14.1. ¹⁹F NMR (CDCl₃) δ−85.1 (s, 3F), −115.2(s, 2F). HRMS calcd. for C₂₃H₁₉ClF₅NO: 456.1154 [M+H]⁺, found: 456.1164.

[0395] TheN-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amine(0.4 g, 0.88 mmol) product of EX-18C was dissolved in anhydrousacetonitrile (1.5 mL). R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.22 g,1.94 mmol) and Yb(OTf)₃ (22 mg, 0.035 mmol) were added, and the reactionmixture was stirred under N₂ at 45° C. in a sealed glass tube for 15 h.The reaction mixture was then cooled to room temperature and dilutedwith Et₂O and saturated aqueous NaHCO₃. The layers were separated andthe aqueous layer was extracted with Et₂O. The ether layers werecombined, washed with brine, dried with anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The viscous oil was adsorbed onto silica gel andpurified by column chromatography eluting with hexanes in ethyl acetate(95:5) which gave 0.32 g (64%) of the desired(2R)-3-[(4-chloro-3-ethylphenoxy)phenyl[[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a viscous, colorlessoil. ¹H NMR (CDCl₃) δ7.47 (m, 4H), 7.23 (m, 3H), 6.90 (d, 1H), 6.72 (dd,1H), 6.52 (d, 1H), 6.42 (m, 2H), 4.73 (s, 2H), 4.39 (m, 1H), 3.91 (dd,1H), 3.58 (m, 2H 2.73 (q, 2H), 2.57 (s, 1H), 1.22 (t, 3H). ¹⁹F NMR(CDCl₃) δ−79.2 (s, 3F), −84.9 (s, 3F), −115.2 (s, 2F). HRMS calcd. forC₂₆H₂₂ClF₈NO₂: 568.1290 [M+H]⁺, found: 568.1296.

EXAMPLE 19

[0396]

(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0397] EX-19A) To a solution of 1,3-dinitrobenzene (4.5 g, 0.03 mol) and3-trifluoromethoxy-phenol (4.8 g, 0.03 mol) in 54 mL ofdimethylsulfoxide was added cesium carbonate (21.8 g, 0.07 mol). Thereaction mixture was heated at 100° C. under nitrogen overnight thencooled to room temperature. The reaction mixture was diluted with waterand extracted with diethyl ether several times. The organic layers werecombined, washed with 1 N HCl and water, dried over MgSO₄, andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel eluting with 1:9 ethyl acetate in hexane toafford 3.0 g (38%) of the desired3-(3-trifluoro-methoxyphenoxy)nitrobenzene product as a yellow-orangeliquid which was 85% pure by reverse phase HPLC analysis. This materialwas carried on without further purification.

[0398] EX-19B) To a solution of3-(3-trifluoromethoxyphenoxy)nitrobenzene (3.0 g, 0.01 mol) from EX-19Ain 100 mL of glacial acetic acid was added zinc metal (6.6 g, 0.1 mol)at room temperature, and the resultant mixture was stirred for 1 h. Thereaction mixture was filtered through celite. The filtrate wasneutralized with ammonium hydroxide and extracted with diethyl etherthen ethyl acetate. The combined organic layers were dried over MgSO₄and concentrated in vacuo. The crude product was purified by columnchromatography on silica gel eluting with 1:9 ethyl acetate in hexane toafford 1.2 g (44%) of the desired 3-(3-trifluoromethoxyphenoxy)anilineproduct as a yellow oil which was 98% pure by reverse phase HPLCanalysis. Anal. calcd. for C₁₃H₁₀F₃NO₂: C, 58.00; H, 3.74; N, 5.20.found: C, 57.68; H, 3.57; N, 5.14. HRMS calcd.: 270.0742 [M+H]⁺, found:270.0767.

[0399] EX-19C) To a solution of 3-(3-trifluoromethoxyphenoxy)aniline(1.0 g, 3.7 mmol) from EX-19B and3-(1,l,2,2-tetrafluoroethoxy)benzaldehyde (0.83 g, 3.7 z. mmol) in 18.5mL of dichloroethane was added sodium triacetoxyborohydride (1.0 g, 4.7mmol) and glacial acetic acid (0.25 mL, 4.3 mmol). The reaction mixturewas stirred at room temperature overnight then quenched with saturatedaqueous sodium bicarbonate and extracted with methylene chloride. Theorganic layer was dried over MgSO₄ and concentrated in vacuo to give 1.8g (100%) of the desired[3-(3-trifluoromethoxy-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amine product as a yellow oil, which was greater than 90% pure byreverse phase HPLC analysis. HRMS calcd. for C₂₂H₁₆F₇NO₃: 476.1097[M+H]⁺, found: 476.1069. This material was carried on to the next stepwithout further purification.

[0400] A solution of[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amine(1.8 g, 3.7 mmol) from EX-19C, R-(+)-1,1,1-trifluoro-2,3-epoxy-propane(0.57 g, 5.2 mmol), and ytterbium (III) trifluoromethanesulfonate (0.24g, 0.38 mmol) in 2.0 mL of acetonitrile was heated at 40° C. in a sealedglass tube overnight. At this time reverse phase HPLC analysis indicatedthat the reaction was only 50% complete. Additional ytterbium (III)trifluoromethanesulfonate and R-(+)-1,1,1l-trifluoro-2,3-epoxypropane(0.26 g, 2.3 mmol) were added to the reaction mixture and again heatedat 40° C. in a sealed glass tube for 48 h. The reaction mixture wascooled to room temperature then diluted with water and methylenechloride and extracted. The organic layer was washed with brine, driedover MgSO₄, and concentrated in vacuo The crude product was purified byreverse phase HPLC eluting with 30% to 90% acetonitrile in water toafford 1.25 g (23%) of the desired(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as yellow-brown oil (90% ee by chiral HPLC analysis). HRMScalcd. for C₂₅H₁₉F₁₀NO₄: 588.1233 [M+H]⁺, found: 588.1225. ¹H NMR(CDCl₃) δ7.35−7.18 (m, 3H), 7.12 (t, 2H), 7.01 (s, 1H), 6.93 (d, 1H),6.85 (d, 1H), 6.82 (s, 1H), 6.56 (dd, 1H), 6.47 (dd, 1H), 6.41 (s, 1H),5.88 (t, 1H), 4.66 (s, 2H), 4.35 (m, 1H), 3.86 (d, 1H), 3.59 (dd, 1H),2.02 (s, 1H). ¹⁹F NMR (CDCl₃) δ−58.31 (s, 3F), −79.24 (d, 3F), −88.57(m, 2F), −137.16 (dt, 2F).

EXAMPLE 20

[0401]

(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxylphenyl]amino]-1,1,1-trifluoro-2-propanol

[0402] EX-20A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) in 100 mLof 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reactionmixture was stirred at room temperature for 6 h then quenched with waterand extracted with dichloromethane. The organic layer was washed withsaturated aqueous sodium bicarbonate, dried over MgSO₄, and concentratedin vacuo to give 11.82 g (83%) of the desired3-[[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]phenol product asa dark orange oil. ¹H NMR (acetone-d₆) δ7.01-7.38 (m, 5H), 6.26-6.44 (m,3H), 6.08 (t, 1H), 5.88 (tt, 1H), 4.34 (s, 2H).

[0403] EX-20B) A solution of3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino] phenol (5.1 g,16.2 mmol) from EX-20A, R-(+)-1,1,1-trifluoro-2,3-epoxypropane (1.5 mL,17.4 mmol), and ytterbium trifluoromethanesulfonate (1.0 g, 10 mol %) in10 mL of acetonitrile was heated at 50° C. in a sealed glass tube for 4h. The reaction mixture was cooled to room temperature, then dilutedwith water and diethyl ether and extracted. The ether layer was washedwith saturated aqueous sodium bicarbonate and brine, dried over MgSO₄,and concentrated in vacuo to give 5.64 g (81%) of the desired(2R)-3-[[[3-(l,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxy-propyl)amino]-phenolproduct as a yellow oil. ¹H NMR (acetone-d₆) δ7.41 (t, 1H), 7.23 (d,1H), 7.16-7.20 (m, 2H), 6.97 (t, 1H), 6.42 (tt, 1H), 6.18-6.24 (m, 3H),4.77 (s, 2H), 4.43-4.48 (m, 1H), 3.58 (dd, 1H), 3.39 (dd, 1H).

[0404] To a solution of(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxypropyl)amino]phenol(100 mg, 0.23 mmol) from EX-20B and 3-trifluoromethylbenzyl bromide(70.0 mg, 0.27 mmol) in 2.5 mL of acetone was added cesium carbonate(100 mg, 0.31 mmol). The reaction mixture was heated at 60° C. for 18 hthen cooled to room temperature. The reaction mixture was filteredthrough celite, and the filtrate was concentrated. The residue waspurified by reverse phase HPLC eluting with 50% to 90% acetonitrile inwater to afford 63.3 mg (45%) of the desired(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanolproduct as an orange oil. HRMS calcd. for C₂₆H₂₁F₁₀NO₃: 586.1440 [M+H]⁺,found: 586.1419. ¹H NMR (acetone-d₆) δ7.61-7.82 (m, 4H), 7.41 (t, 1H),7.25 (d, 1H), 7.10-7.21 (m, 3H), 6.34-6.67 (m, 4H), 5.73 (d, 1H), 5.19(s, 2H), 4.82 (s, 2H), 4.34-4.48 (m, 1H), 3.99 (dd, 1H), 3.68 (dd, 1H).

[0405] Additional examples of(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]-[3-[[aryl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin. Example Table 4.

Example Table 4.(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[aryl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanols

[0406]

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 213,5-difluorobenzyl 554.1378 554.1352 22 3-trifluoromethoxybenzyl602.1389 602.1390 23 3-isopropyl 470.1566 464.1601

EXAMPLE 24

[0407]

(2R)-3-[[3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl][[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol

[0408](2R)-3-[[3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolcan be prepared by one skilled in the art using similar methods startingfrom 3-(trifluoromethoxy)-benzaldehyde. HRMS calcd. forC₂₅H₂₀F₉NO₄:570.1327 [M+H]⁺, found: 570.1325. ¹H NMR (acetone-d₆) δ7.43(t, 1H), 7.32 (d, 1H), 7.18-7.23 (m, 2H), 7.01-7.16 (m, 3H), 6.92-7.00(m, 1H), 6.38-6.45 (m, 3H), 5.12 (s, 2H), 4.81 (s, 2H), 4.41-4.53 (m,1H), 3.98 (dd, 1H), 3.63 (dd, 1H).

[0409] Additional examples of(2R)-3-[[3-[[aryl]methoxy]phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolscan be prepared by one skilled in the art using similar methods, asshown in Example Table 5.

Example Table 5.(2R)-3-[[3-[[aryl]methoxy]phenyl][[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

[0410]

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 254-trifluoromethoxybenzyl 570.1327 570.1299 26 3,5- 622.1252 622.1252di(trifluoromethyl)benzyl 27 3-trifluoromethylbenzyl 554.1378 554.136928 3,5-difluorobenzyl 522.1315 522.1259 29 benzyl 486.1504 486.1504 30isopropyl 438.1504 438.1509 31 cyclohexylmethyl 492.1973 492.1973 32cyclopentyl 464.1660 464.1641

EXAMPLE 33

[0411]

(2R)-3-[[3-(4-fluoro-3-methylphenoxy)phenyl][[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0412] EX-33A) To a solution of 3-bromoaniline (5.7 mL, 52.6 mmol) and3-trifluoro-methoxybenzaldehyde (10.0 g, 52.6 mmol) in 135 mL ofdichloroethane was added sodium triacetoxyborohydride (14.5 g, 68.4mmol) and glacial acetic acid (3.1 mL, 54.7 mmol). The reaction wasstirred at room temperature for 2 h, then quenched with water andextracted with dichloromethane. The organic layer was washed withsaturated aqueous sodium bicarbonate, dried over MgSO₄, and concentratedin vacuo. The crude product was purified by column chromatography onsilica gel eluting with 1:9 ethyl acetate in hexane to give 14.3 g (78%)of the desired of N-(3-bromophenyl)[[3-(trifluoromethoxy)phenyl]methyl]amine product as a dark brown oil. HRMS calcd. forC₁₄H₁₁BrF₃NO: 346.0055 [M+H]⁺, found: 346.0052.

[0413] EX-33B) A solution of ofN-(3-bromophenyl)[[3-(trifluoromethoxy)phenyl]methyl]-amine (10.0 g,28.9 mmol) from EX-33A, R-(+)-1,1,1-trifluoro-2,3-epoxypropane (4.2 g,37.6 mmol), and ytterbium (III) trifluoromethanesulfonate (1.79 g, 2.89mmol) in 27 mL of acetonitrile was heated at 50° C. in a sealed glasstube overnight. The reaction mixture was cooled to room temperature andfiltered through celite. The crude product was purified by columnchromatography on silica gel eluting with 2:3 dichloromethane in hexaneto afford 11.9 g (90%) of the desired(2R)-3-[[(3-bromophenyl)][[3-(tri-fluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a brown oil (98% ee by chiral HPLC analysis). HRMS calcd. forC₁₇H₁₄BrF₆NO₂: 458.0190 [M+H]⁺, found: 458.0197.

[0414] A suspension of 4-fluoro-3-methylphenol (98.0 μL, 0.88 mmol) andcesium carbonate (319.5 mg, 0.98 mmol) in 1 mL of N,N-dimethylacetamidewas preheated at 60° C. for 5 minutes. To this solution was added 4 mLof a stock solution containing(2R)-3-[[(3-bromophenyl)][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.437 mmol) fromEX-33B, 1-naphthoic acid (164 mg, 0.95 mmol), copper(I)trifluoromethansulfonate benzene complex (21.8 mg, 0.0434 mmol), 4 Åsieves (105 mg), and 4 mL of toluene. The reaction mixture was stirredat 105° C. for 3 weeks and 2 days. During that time, additional cesiumcarbonate and catalyst were added (a spatula tip of each) to thereaction three different times. The reaction was cooled to roomtemperature, filtered through celite, and the solvent was evaporated.The residue was purified by reverse phase HPLC eluting with 35% to 90%acetonitrile in water to afford 50.5 mg (23%) of the desired(2R)-3-[[3-(4-fluoro-3-methylphenoxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMScalcd. for C₂₄H₂₀F₇NO₃: 504.1410 [M+H]⁺, found: 504.1389. ¹H NMR(acetone-d₆) δ7.44 (t, 1H), 7.24 (d, 1H), 7.08-7.21 (m, 3H), 6.98 (t,1H), 6.75-6.85 (m, 1H), 6.68-6.74 (m, 1H), 6.53 (d, 1H), 6.21-6.34 (m,2H), 4.79 (t, 2H), 4.46-4.53 (m, 1H), 3.95 (dd, 1H), 2.61-2.72 (m, 1H),2.20 (s, 3H).

[0415] Additional examples(2R)-3-[[(aryloxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolscan be prepared by one skilled in the art using similar methods, asshown in Example Table 6.

Example Table 6.(2R)-3-[[(aryloxy)phenyl][[3-(trifluoromethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

[0416]

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 343-trifluoromethoxy 556.1170 556.1180 35 3-isopropyl 514.1817 514.1823 363,4-dimethyl 500.1660 500.1654 37 4-chloro-3-methyl 520.1114 520.1129 383-tert-butyl 528.1973 528.1942 39 3,4-dichloro 540.0568 540.0567 403,4-(CH₂CH₂CH₂CH₂)— 526.1817 526.1788

EXAMPLE 41

[0417]

(2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0418] EX41A) To a solution of p-cresol (5.76 g, 0.053 mol) and1,3-dinitrobenzene (8.97 g, 0.053 mol) in 100 mL of dimethylsulfoxidewas added cesium carbonate (43.4 g, 0.133 mol). The reaction mixture washeated at 100° C. for 18 h, then cooled to room temperature, quenchedwith water, and extracted with diethyl ether. The organic layers werecombined, washed with 0.1 N HCl and water, dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel eluting with 1:4 ethyl acetate in hexane toafford 8.0 g (66%) of the desired 3-(4-methylphenoxy)nitrobenzeneproduct as a yellow oil. ¹H NMR (CDCl₃) δ7.83 (s, 1H), 7.64 (t, 1H),7.32 (d, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 6.8 (d, 2H), 2.20 (s, 1H).

[0419] EX-41B) A solution of 3-(4-methylphenoxy)nitrobenzene (8.0 g,0.035 mol) from EX41A in 25 mL of ethanol under nitrogen was chargedwith 10% palladium on carbon (0.80 g). The resulting mixture washydrogenated for 4 h at room temperature and 45 psi. The reactionmixture was filtered through celite and concentrated in vacuo to give6.7 g (96%) of the desired 3-(4-methylphenoxy)aniline product as ayellow oil. ESMS m/z=200 [M+H]⁺ confirmed the desired C₁₃H₁₃NO productand the complete consumption of starting material.

[0420] EX-41C) To a solution of 3-(4-methylphenoxy)aniline (2.91 g,0.015 mol) from EX-41B, and 3-(trifluoromethoxy)benzyaldehyde (3.24 g,0.015 mol) in 50 mL dichloroethane was added sodiumtriacetoxyborohydride (4.02 g, 0.019 mol) and glacial acetic acid (0.99g, 0.017 mol). The reaction mixture was stirred at room temperature for18 h, then quenched with saturated aqueous sodium bicarbonate andextracted with dichloromethane. The organic layers were combined, driedover MgSO₄ and concentrated in vacuo to give 5.38 g (91%) of the desiredN-[3-(4-methylphenoxy)-phenyl)]-[[3-(trifluoromethoxy)phenyl]methyl]amineproduct as an orange oil. ESMS nm/z=374 [M+H]⁺ confirmed the desiredC₂₁H₁₈NO₂F₃ product and the complete consumption of starting material.

[0421] To a mixture ofN-[3-(4-methylphenoxy)phenyl)]-[[3-(trifluoromethoxy)-phenyl]-methyl]amine(l.3g, 0.0035 mol) from EX-41C and R-(+)-1,1,1-trifluoro-2,3-epoxypropane(0.59 g, 0.0053 mol) was added a suspension of ytterbium (III)trifluoromethanesulfonate (0.22 g, 0.0004 mol) in 1.3 ML ofacetonitrile. The resulting mixture was heated at 50° C. in a sealedglass tube for 18 h. The reaction mixture was cooled to roomtemperature, then diluted with water and extracted with ethyl acetate.The crude product was purified by column chromatography on silica geleluting with 1:4 ethyl acetate in hexane to afford 1.03 g (61%) of thedesired (2R)-3-[3-(4-methyl-phenoxy)phenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propa-nol product as a pure yellow oil.Anal. calcd. for C₂₄H₂₁F₆NO₃: C, 59.38; H, 4.36; N, 2.89. Found: C,59.17; H, 4.62; N, 2.80. HRMS calcd.: 486.1504 [M+H]⁺, found: 486.1513.¹H NMR (C₆D₆) δ6.82 (m, 8H), 6.60 (dd, 1H), 6.42 (dd, 1H), 6.38 (s,1H),. 6.18 (dd, 1H), 4.00 (s, 2H), 3.63 (m, 1H), 3.40 (d, 1H), 3.02 (m,1H), 2.00 (s, 3H), 1.40 (d, 1H). ¹⁹F NMR (C₆D₆) δ−57.98 (s, 3F), −78.50(s, 3F).

[0422] Additional examples of(2R)-3-[3-(substituted-phenoxy)phenyl]-[[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolscan prepared by one skilled in the art using similar methods, as shownin Example Table 7.

Example Table 7.(2R)-3-[3-(substituted-phenoxy)phenyl][[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

[0423]

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 424-fluoro 490.1253 490.1238

EXAMPLE 43

[0424]

(2R)-3-[[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0425] EX43A) To a solution of 3-aminophenol (5 g, 46 mmol),1-bromo-2,4-difluorobenzene (10 g, 50 mmol) and Cs₂CO₃ (16 g, 50 mmol)in 25 mL of dimethylformamide was added solid (CuOTf)₂C₆H₆ (100 mg), andthe mixture was stirred under nitrogen at 85° C. for 22 h, at which timeHPLC analysis indicated that the reaction had gone to completion andformed two products. The DMF was removed under reduced pressure. Theresidue was diluted with ether and filtered through a celite pad. Thepad was washed with ether and a small amount of water. The mixture wasextracted with ether several times. The combined ether layers werewashed with water and brine, then dried over MgSO₄. The dried organiclayer was evaporated to give 10.2 g (80%) of the desired product, whichconsisted of a 11:1 ratio of 3-(2-bromo-5-fluoro-phenoxy)aniline and3-(4-bromo-3-fluorophenoxy)aniline. The crude product was purified byflash column chromatography on silica gel eluting with 1:7:0.01 of ethylacetate:hexane:ammonium hydroxide to give 8.8 g (68%) of the desiredproduct as a yellow oil, which was a 25:1 ratio of3-(2-bromo-5-fluorophenoxy)aniline and3-(4-bromo-3-fluorophenoxy)aniline. HRMS calcd. for C₁₂H₉NOFBr: 281.9930[M+H]⁺, found: 281.9950.

[0426] EX43B) The 3-(2-bromo-5-fluorophenoxy)aniline (1.39 g, 4.95 mmol)product from EX43A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.0 g,4.5 mmol) were dissolved in 15 mL of dichloroethane and acetic acid(0.30 mL, 5.4 mmol), then solid NaBH(OAc)₃ (1.26 g, 5.9 mmol) was added.The mixture was stirred at room temperature for 1 h, then quenched withwater and extracted with ether. The ether layer was washed with waterand brine, then dried over MgSO₄, and evaporated to give 2.1 g (97%) ofcrude product, which was purified by flash column chromatography onsilica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammoniumhydroxide to give 2.0 g (91%) of the desired3-[3-(2-bromo-5-fluoro-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amineproduct, as a light yellow oil, >90% pure by HPLC analysis. HRMS calcd.for C₂₁H₁₅NO₂BrF₅: 488.0285 [M+H]⁺, found: 488.0269.

[0427] The3-[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-methyl]amine(0.5 g, 2.0 mmol) product from EX43B andR-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.17 g, 2.0 mmol) from EXA weredissolved in 0.5 mL of acetonitrile. Ytterbium (III)trifluoromethanesulfonate (0.06 g, 0.1 mmol) was added, and the stirredsolution was warmed to 40° C. for 1 h, at which time HPLC analysisindicated that no secondary amine starting material remained. Thereaction was quenched with water and extracted with ether. The etherlayer was washed with water and brine, then dried over MgSO₄. The crudeproduct was purified by flash column chromatography on silica geleluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give0.4 g (67%) of the desiredR-(+)-3-[[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a light yellow oil (>84% ee by chiral HPLC analysis). Anal.calcd. for C₂₄H₁₈BrF₈NO₃: C, 48.02; H, 3.02; N, 2.33. found: C, 48.07;H, 3.14; N, 2.31. HRMS calcd.: 600.0420 [M+H]⁺, found: 600.0386. ¹H NMR(CDCl₃) δ7.5 0 (dd, 1H), 7.30 (t, 1H), 7.18 (t, 1H), 7.07 (t, 2H), 6.99(s, 1H), 6.70 (dt, 1H), 6.56 (dd, 1H), 6.52 (dd, 1H), 6.38 (dd, 1H),6.32 (m, 1H), 5.87 (tt, 1H,), 4.65 (d, 2H), 4.33 (m, 1H), 3.85 (dd, 1H),3.56 (dd, 1H), 2.48 (bs, 1H). NOE difference spectra confirmed that theisolated material was the indicatedN-[3-(2-bromo-5-fluoro-phenoxy)phenyl]-3-aminopropanol product. ¹⁹F NMR(CDCl₃) δ−79.24 (d, 3F), −88.57 (m, 2F), −112.04 (q, 1H), −137.16 (dt,2F).

EXAMPLE 44

[0428]

(2R)-N-[2-chloro-6-(p-fluorophenoxy)-1,3,5-triazin-4-yl]-3-[[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

[0429] EX44A) 3-Trifluoromethoxybenzenemethanamine (1.15 g, 6 mmol) andR-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.67 g, 6 mmol) were combinedand stirred at 80° C. for 1.5 h. The mixture was cooled to roomtemperature, and the resulting solid was recrystallized from hothexanes. The white solid was isolated by vacuum filtration and washedwith cold hexanes to give 0.67 g (37%) of pure(2R)-3-[[[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.¹H NMR (CDCl₃) δ7.37 (t, 1H), 7.24 (d, 1H), 7.15 (m, 2H), 3.99 (m, 1H),3.85 (d, 2H), 2.98 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 1H). ¹⁹F NMR(CDCl₃) δ−58.19 (s, 3F), −78.88 (s, 3F). HRMS calcd. for C₁₁H₁₁F₆NO₂:304.0772 [M+H]⁺, found: 304.0794.

[0430] EX-44B) To a solution of p-fluorophenol 1.00 g (8.92 mmol) in 30mL of tetrahydrofuran at 0° C. was added a 60% dispersion of sodiumhydride in mineral oil (0.36 g, 8.92 mmol). After 30 min, cyanuricchloride (1.64 g, 8.92 mmol) was added as a heterogeneous mixture intetrahydrofuran at 0° C. The reaction mixture was allowed to slowly warmto room temperature. After 14 h, the mixture was cooled to 0° C., and asaturated aqueous NH₄Cl solution was added. The aqueous solution wasextracted with diethyl ether (3×50 mL). The combined ether extracts werewashed with brine, dried (MgSO₄), and concentrated in vacuo to afford1.34 g (58%) of the desired2,4-dichloro-6-(4-fluorophenoxy)-1,3,5-triazine product as an off whitesolid which was taken on to the next step without purification. MSm/z=260 [M+H]⁺.

[0431] To a stirred solution of aminopropanol from EX44A (0.100 g, 0.330mmol) in N,N-dimethylformamide at 0° C. was added the2,4-dichloro-(4-fluorophenoxy)-1,3,5-triazine ether product from EX44B(0.086 g, 0.330 mmol) as a solution in N,N-di-methylformamide. Thereaction mixture was allowed to slowly warm to room temperature. After14 h, the reaction mixture was cooled to 0° C., and a saturated aq.NaHCO₃ solution was added. After stirring the reaction mixture for 30min at room temperature, the aqueous layer was extracted with ether(3×30 mL). The combined ether extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give a yellow oil. The cruderesidue was purified by column chromatography on silica gel eluting with20% ethyl acetate in hexanes to give 0.075 g (43%) of the desired(2R)-N-[2-chloro-6-(p-fluorophenoxy)-1,3,5-triazin-4-yl]-3-[[[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanolproduct as a pale yellow oil. HRMS calcd. for C₂₀H₁₄ClF₇N₄O₃: 526.0643[M ]⁺, found: 526.0632. ¹H NMR (C₆D₆) δ6.95 (s, 1H), 6.63 (m, 14H), 4.74(d, 1H), 4.37 (d, 1H), 4.16 (d, 1H), 4.00 (d, 2H), 3.73 (m, 1H), 3.48(m, 2H), 3.26 (m, 2H), 3.12 (m, 2H).

[0432] Based on the preceding procedures, additional substituted(2R)-3-[(N-aryl)-[[aryl]methyl]amino]-1,1,1-trifluoro-2-propanols areprepared by one skilled in the art using similar methods, as shown inExample Table 8. Substituted (3R)-4-[N-(aryl)-[(aryl)methyl]amino]-1,1,1,2,2-pentafluoro-3-butanols are prepared by one skilled in the art usingsimilar methods, as shown in Example Table 9. Substituted(2R)-3-[N-(aryl)[(aryl)oxy]amino]-1,1,1-trifluoro-2-propanols areprepared by one skilled in the art using similar methods, as shown inExample Table 10. Substituted(2R)-3-[N-(aryl)-[(aryl)methyl]amino]-1,1-difluoro-1-chloro-2-propanolsare prepared by one skilled in the art using similar methods, as shownin Example Table 11. Substituted(2R)-3-[N,N′-(diaryl)amino]-1,1,1-trifluoro-2-propanols are prepared byone skilled in the art using similar methods, as shown in Example Table12.

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 45 3-isopropyl 69 3-CF₃O-benzyloxy 462-Cl, 3-Cl 70 3-CF₃-benzyloxy 47 3-CF₃O 71 3-F, 5-F-benzyloxy 48 4-F 72cyclohexylmethyleneoxy 49 4-CH₃ 73 benzyloxy 50 2-F, 5-Br 74 3-CF₃,5-CF₃-benzyloxy 51 3-CF₃CF₂ 75 4-CF₃O-benzyloxy 52 3-CH₃CH₂ 764-CH₃CH₂-benzyloxy 53 3-CH₃, 5-CH₃ 77 isopropoxy 54 3-(CH₃)₃C 783-CF₃-benzyl 55 4-F, 3-CH₃ 79 isopropylthio 56 3-Cl, 4-Cl 80cyclopentoxy 57 3,4-(CH₂)₄ 81 3-Cl-5-pyridinyloxy 58 3-HCF₂CF₂O 823-CF₃S-benzyloxy 59 3-CHF₂O 83 3-CH₃, 4-CH₃-benzyloxy 60 3-(CH₃)₂N 842-F, 3-CF₃-benzyloxy 61 3-cyclopropyl 85 3-F, 5-CF₃-benzyloxy 623-(2-furyl) 86 4-(CH₃)₂CH-benzyloxy 63 3-CF₃CF₂ 87 1-phenylethoxy 644-NH₂ 88 4-F, 3-CH₃-benzoyl 65 3-CH₃, 4-CH₃, 5-CH₃ 89 3-CF₃-phenyl 664-CH₃CH₂CH₂O 90 4-CH₃O-phenylamino 67 3-CF₃ 91 cyclopropoxy 68 2-NO₂ 924-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 93 3-isopropyl 117 3-CF₃O-benzyloxy 942-Cl, 3-Cl 118 3-CF₃-benzyloxy 95 3-CF₃O 119 3-F, 5-F-benzyloxy 96 4-F120 cyclohexylmethyleneoxy 97 4-CH₃ 121 benzyloxy 98 2-F, 5-Br 1223-CF₃, 5-CF₃-benzyloxy 99 4-Cl, 3-CH₃CH₂ 123 4-CF₃O-benzyloxy 1003-CH₃CH₂ 124 4-CH₃CH₂-benzyloxy 101 3-CH₃, 5-CH₃ 125 isopropoxy 1023-(CH₃)₃C 126 3-CF₃-benzyl 103 4-F, 3-CH₃ 127 isopropylthio 104 3-Cl,4-Cl 128 cyclopentoxy 105 3,4-(CH₂)₄ 129 3-Cl-5-pyridinyloxy 1063-HCF₂CF₂O 130 3-CF₃S-benzyloxy 107 3-CHF₂O 131 3-CH₃, 4-CH₃-benzyloxy108 3-(CH₃)₂N 132 2-F, 3-CF₃-benzyloxy 109 3-cyclopropyl 133 3-F,5-CF₃-benzyloxy 110 3-(2-furyl) 134 4-(CH₃)₂CH-benzyloxy 111 3-CF₃CF₂135 1-phenylethoxy 112 4-NH₂ 136 4-F, 3-CH₃-benzoyl 113 3-CH₃, 4-CH₃,5-CH₃ 137 3-CF₃-phenyl 114 4-CH₃CH₂CH₂O 138 4-CH₃O-phenylamino 115 3-CF₃139 cyclopropoxy 116 2-NO₂ 140 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 141 3-isopropyl 165 3-CF₃O-benzyloxy142 2-Cl, 3-Cl 166 3-CF₃-benzyloxy 143 3-CF₃O 167 3-F, 5-F-benzyloxy 1444-F 168 cyclohexylmethyleneoxy 145 4-CH 169 benzyloxy 146 2-F, 5-Br 1703-CF₃, 5-CF₃-benzyloxy 147 4-Cl, 3-CH₃CH₂ 171 4-CF₃O-benzyloxy 1483-CH₃CH₂ 172 4-CH₃CH₂-benzyloxy 149 3-CH₃, 5-CH₃ 173 isopropoxy 1503-(CH₃)₃C 174 3-CF₃-benzyl 151 4-F, 3-CH₃ 175 isopropylthio 152 3-Cl,4-Cl 176 cyclopentoxy 153 3,4-(CH₂)₄ 177 3-Cl-5-pyridinyloxy 1543-HCF₂CF₂O 178 3-CF₃S-benzyloxy 155 3-CHF₂O 179 3-CH₃, 4-CH₃-benzyloxy156 3-(CH₃)₂N 180 2-F, 3-CF₃-benzyloxy 157 3-cyclopropyl 181 3-F,5-CF₃-benzyloxy 158 3-(2-furyl) 182 4-(CH₃)₂CH-benzyloxy 159 3-CF₃CF₂183 1-phenylethoxy 160 4-NH₂ 184 4-F, 3-CH₃-benzoyl 161 3-CH₃, 4-CH₃,5-CH₃ 185 3-CF₃-phenyl 162 4-CH₃CH₂CH₂O 186 4-CH₃O-phenylamino 163 3-CF₃187 cyclopropoxy 164 2-NO₂ 188 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 189 3-isopropyl 213 3-CF₃O-benzyloxy190 2-Cl, 3-Cl 214 3-CF₃-benzyloxy 191 3-CF₃O 215 3-F, 5-F-benzyloxy 1924-F 216 cyclohexylmethyleneoxy 193 4-CH₃ 217 benzyloxy 194 2-F, 5-Br 2183-CF₃, 5-CF₃-benzyloxy 195 4-Cl, 3-CH₃ 219 4-CF₃O-benzyloxy 196 3-CH₃CH₂220 4-CH₃CH₂-benzyloxy 197 3-CH₃, 5-CF₃ 221 isopropoxy 198 3-(CH₃)₃C 2223-CF₃-benzyl 199 4-F, 3-CH₃ 223 isopropylthio 200 3-Cl, 4-Cl 224cyclopentoxy 201 3,4-(CH₂)₄ 225 3-Cl-5-pyridinyloxy 202 3-HCF₂CF₂O 2263-CF₃S-benzyloxy 203 3-CHF₂O 227 3-CH₃, 4-CH₃-benzyloxy 204 3-(CH₃)₂N228 2-F, 3-CF₃-benzyloxy 205 3-cyclopropyl 229 3-F, 5-CF₃-benzyloxy 2063-(2-furyl) 230 4-(CH₃)₂CH-benzyloxy 207 3-CF₃CF₂ 231 1-phenylethoxy 2084-NH₂ 232 4-F, 3-CH₃-benzoyl 209 3-CH₃, 4-CH₃, 5-CH₃ 233 3-CF₃-phenyl210 4-CH₃CH₂CH₂O 234 4-CH₃O-phenylamino 211 3-CF₃ 235 cyclopropoxy 2122-NO₂ 236 4-NO₂-phenylthio

Ex. No. R_(SUB1) No. R_(SUB2) 237 3-isopropyl 261 3-CF₃O-benzyloxy 2382-Cl, 3-Cl 262 3-CF₃-benzyloxy 239 3-CF₃O 263 3-F, 5-F-benzyloxy 240 4-F264 cyclohexylmethyleneoxy 241 4-CH₃ 265 benzyloxy 242 2-F, 5-Br 2663-CF₃, 5-CF₃-benzyloxy 243 4-Cl, 3-CH₃ 267 4-CF₃O-benzyloxy 244 3-CH₃CH₂268 4-CH₃CH₂-benzyloxy 245 3-CH₃, 5-CH₃ 269 isopropoxy 246 3-(CH₃)₃C 2703-CF₃-benzyl 247 4-F, 3-CH₃ 271 isopropylthio 248 3-Cl, 4-Cl 272cyclopentoxy 249 3,4-(CH₂)₄ 273 3-Cl-5-pyridinyloxy 250 3-HCF₂CF₂O 2743-CF₃S-benzyloxy 251 3-CHF₂O 275 3-CH₃, 4-CH₃-benzyloxy 252 3-(CH₃)₂N276 2-F, 3-CF₃-benzyloxy 253 3-cyclopropyl 277 3-F, 5-CF₃-benzyloxy 2543-(2-furyl) 278 4-(CH₃)₂CH-benzyloxy 255 3-CF₃CF₂ 279 1-phenylethoxy 2564-NH₂ 280 4-F, 3-CH₃-benzoyl 257 3-CH₃, 4-CH₃, 5-CH₃ 281 3-CF₃-phenyl258 4-CH₃CH₂CH₂O 282 4-CH₃O-phenylamino 259 3-CF₃ 283 cyclopropoxy 2602-NO₂ 284 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 285 3-isopropyl 309 3-CF₃O-benzyloxy286 2-Cl, 3-Cl 310 3-CF₃-benzyloxy 287 3-CF₃O 311 3-F, 5-F-benzyloxy 2884-F 312 cyclohexylmethyleneoxy 289 4-CH₃ 313 benzyloxy 290 2-F, 5-Br 3143-CF₃, 5-CF₃-benzyloxy 291 4-Cl, 3-CH₃CH₂ 315 4-CF₃O-benzyloxy 2923-CH₃CH₂ 316 4-CH₃CH₂-benzyloxy 293 3-CH₃, 5-CH₃ 317 isopropoxy 2943-(CH₃)₃C 318 3-CF₃-benzyl 295 4-F, 3-CF₃ 319 isopropylthio 296 3-Cl,4-Cl 320 cyclopentoxy 297 3,4-(CH₂)₄ 321 3-Cl-5-pyridinyloxy 2983-HCF₂CF₂O 322 3-CF₃S-benzyloxy 299 3-CHF₂O 323 3-CH₃, 4-CH₃-benzyloxy300 3-(CH₃)₂N 324 2-F, 3-CF₃-benzyloxy 301 3-cyclopropyl 325 3-F,5-CF₃-benzyloxy 302 3-(2-furyl) 326 4-(CH₃)₂CH-benzyloxy 303 3-CF₃CF₂327 1-phenylethoxy 304 4-NH₂ 328 4-F, 3-CH₃-benzoyl 305 3-CH₃, 4-CH₃,5-CH₃ 329 3-CF₃-phenyl 306 4-CH₃CH₂CH₂O 330 4-CH₃O-phenylamino 307 3-CF₃331 cyclopropoxy 308 2-NO₂ 332 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 333 3-isopropyl 357 3-CF₃O-benzyloxy334 2-Cl, 3-Cl 358 3-CF₃-benzyloxy 335 3-CF₃O 359 3-F, 5-F-benzyloxy 3364-F 360 cyclohexylmethyleneoxy 337 4-CH₃ 361 benzyloxy 338 2-F, 5-Br 3623-CF₃, 5-CF₃-benzyloxy 339 4-Cl, 3-CH₃CH₂ 363 4-CF₃O-benzyloxy 3403-CH₃CH₂ 364 4-CH₃CH₂-benzyloxy 341 3-CH₃, 5-CH₃ 365 isopropoxy 3423-(CH₃)₃C 366 3-CF₃-benzyl 343 4-F, 3-CH₃ 367 isopropylthio 344 3-Cl,4-Cl 368 cyclopentoxy 345 3,4-(CH₂)₄ 369 3-Cl-5-pyridinyloxy 3463-HCF₂CF₂O 370 3-CF₃S-benzyloxy 347 3-CHF₂O 371 3-CH₃, 4-CH₃-benzyloxy348 3-(CH₃)₂N 372 2-F, 3-CF₃-benzyloxy 349 3-cyclopropyl 373 3-F,5-CF₃-benzyloxy 350 3-(2-furyl) 374 4-(CH₃)₂CH-benzyloxy 351 3-CF₃CF₂375 1-phenylethoxy 352 4-NH₂ 376 4-F, 3-CH₃-benzoyl 353 3-CH₃, 4-CH₃,5-CH₃ 377 3-CF₃-phenyl 354 4-CH₃CH₂CH₂O 378 4-CH₃O-phenylamino 355 3-CF₃379 cyclopropoxy 356 2-NO₂ 380 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 381 3-isopropyl 405 3-CF₃O-benzyloxy382 2-Cl, 3-Cl 406 3-CF₃-benzyloxy 383 3-CF₃O 407 3-F, 5-F-benzyloxy 3844-F 408 cyclohexylmethyleneoxy 385 4-CH₃ 409 benzyloxy 386 2-F, 5-Br 4103-CF₃, 5-CF₃-benzyloxy 387 4-Cl, 3-CH₃CH₂ 411 4-CF₃O-benzyloxy 3883-CH₃CH₂ 412 4-CH₃CH₂-benzyloxy 389 3-CH₃, 5-CH₃ 413 isopropoxy 3903-(CH₃)₃C 414 3-CF₃-benzyl 391 4-F, 3-CH₃ 415 isopropylthio 392 3-Cl,4-Cl 416 cyclopentoxy 393 3,4-(CH₂)₄ 417 3-Cl-5-pyridinyloxy 3943-HCF₂CF₂O 418 3-CF₃S-benzyloxy 395 3-CHF₂O 419 3-CH₃, 4-CH₃-benzyloxy396 3-(CH₃)₂N 420 2-F, 3-CF₃-benzyloxy 397 3-cyclopropyl 421 3-F,5-CF₃-benzyloxy 398 3-(2-furyl) 422 4-(CH₃)₂CH-benzyloxy 399 3-CF₃CF₂423 1-phenylethoxy 400 4-NH₂ 424 4-F, 3-CH₃-benzoyl 401 3-CH₃, 4-CH₃,5-CH₃ 425 3-CF₃-phenyl 402 4-CH₃CH₂CH₂O 426 4-CH₃O-phenylamino 403 3-CF₃427 cyclopropoxy 404 2-NO₂ 428 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 429 3-isopropyl 453 3-CF₃O-benzyloxy430 2-Cl, 3-Cl 454 3-CF₃-benzyloxy 431 3-CF₃O 455 3-F, 5-F-benzyloxy 4324-F 456 cyclohexylmethyleneoxy 433 4-CH₃ 457 benzyloxy 434 2-F, 5-Br 4583-CF₃, 5-CF₃-benzyloxy 435 4-Cl, 3-CH₃CH₂ 459 4-CF₃O-benzyloxy 4363-CH₃CH₂ 460 4-CH₃CH₂-benzyloxy 437 3-CH₃, 5-CH₃ 461 isopropoxy 4383-(CH₃)₃C 462 3-CF₃-benzyl 439 4-F, 3-CH₃ 463 isopropylthio 440 3-Cl,4-Cl 464 cyclopentoxy 441 3,4-(CH₂)₄ 465 3-Cl-5-pyridinyloxy 4423-HCF₂CF₂O 466 3-CF₃S-benzyloxy 443 3-CHF₂O 467 3-CH₃, 4-CH₃-benzyloxy444 3-(CH₃)₂N 468 2-F, 3-CF₃-benzyloxy 445 3-cyclopropyl 469 3-F,5-CF₃-benzyloxy 446 3-(2-furyl) 470 4-(CH₃)₂CH-benzyloxy 447 3-CF₃CF₂471 1-phenylethoxy 448 4-NH₂ 472 4-F, 3-CH₃-benzoyl 449 3-CH₃, 4-CH₃,5-CH₃ 473 3-CF₃-phenyl 450 4-CH₃CH₂CH₂O 474 4-CH₃O-phenylamino 451 3-CF₃475 cyclopropoxy 452 2-NO₂ 476 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 477 3-isopropyl 501 3-CF₃O-benzyloxy478 2-Cl, 3-Cl 502 3-CF₃-benzyloxy 479 3-CF₃O 503 3-F, 5-F-benzyloxy 4804-F 504 cyclohexylmethyleneoxy 481 4-CH₃ 505 benzyloxy 482 2-F, 5-Br 5063-CF₃, 5-CF₃-benzyloxy 483 4-Cl, 3-CH₃CH₂ 507 4-CF₃O-benzyloxy 4843-CH₃CH₂ 508 4-CH₃CH₂-benzyloxy 485 3-CH₃, 5-CH₃ 509 isopropoxy 4863-(CH₃)₃C 510 3-CF₃-benzyl 487 4-F, 3-CH₃ 511 isopropylthio 488 3-Cl,4-Cl 512 cyclopentoxy 489 3,4-(CH₂)₄ 513 3-Cl-5-pyridinyloxy 4903-HCF₂CF₂O 514 3-CF₃S-benzyloxy 491 3-CHF₂O 515 3-CH₃, 4-CH₃-benzyloxy492 3-(CH₃)₂N 516 2-F, 3-CF₃-benzyloxy 493 3-cyclopropyl 517 3-F,5-CF₃-benzyloxy 494 3-(2-furyl) 518 4-(CH₃)₂CH-benzyloxy 495 3-CF₃CF₂519 1-phenylethoxy 496 4-NH₂ 520 4-F, 3-CH₃-benzoyl 497 3-CH₃, 4-CH₃,5-CH₃ 521 3-CF₃-phenyl 498 4-CH₃CH₂CH₂O 522 4-CH₃O-phenylamino 499 3-CF₃523 cyclopropoxy 500 2-NO₂ 524 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 525 3-isopropyl 549 3-CF₃O-benzyloxy526 2-Cl, 3-Cl 550 3-CF₃-bezyloxy 527 3-CF₃O 551 3-F, 5-F-benzyloxy 5284-F 552 cyclohexylmethyleneoxy 529 4-CH₃ 553 benzyloxy 530 2-F, 5-Br 5543-CF₃, 5-CF₃-benzyloxy 531 4-Cl, 3-CH₃CH₂ 555 4-CF₃O-benzyloxy 5323-CH₃CH₂ 556 4-CH₃CH₂-benzyloxy 533 3-CH₃, 5-CH₃ 557 isopropoxy 5343-(CH₃)₃C 558 3-CF₃-benzyl 535 4-F, 3-CH₃ 559 isopropylthio 536 3-Cl,4-Cl 560 cyclopentoxy 537 3,4-(CH₂)₄ 561 3-Cl-5-pyridinyloxy 5383-HCF₂CF₂O 562 3-CF₃S-benzyloxy 539 3-CHF₂O 563 3-CH₃, 4-CH₃-benzyloxy540 3-(CH₃)₂N 564 2-F, 3-CF₃-benzyloxy 541 3-cyclopropyl 565 3-F,5-CF₃-benzyloxy 542 3-(2-furyl) 566 4-(CH₃)₂CH-benzyloxy 543 3-CF₃CF₂567 1-phenylethoxy 544 4-NH₂ 568 4-F, 3-CH₃-benzoyl 545 3-CH₃, 4-CH₃,5-CH₃ 569 3-CF₃-phenyl 546 4-CH₃CH₂CH₂O 570 4-CH₃O-phenylamino 547 3-CF₃571 cyclopropoxy 548 2-NO₂ 572 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 573 3-isopropyl 597 3-CF₃O-benzyloxy574 2-Cl, 3-Cl 598 3-CF₃-benzyloxy 575 3-CF₃O 599 3-F, 5-F-benzyloxy 5764-F 600 cyclohexylmethyleneoxy 577 4-CH₃ 601 benzyloxy 578 2-F, 5-Br 6023-CF₃, 5-CF₃-benzyloxy 579 4-Cl, 3-CH₃CH₂ 603 4-CF₃O-benzyloxy 5803-CH₃CH₂ 604 4-CH₃CH₂-benzyloxy 581 3-CH₃, 5-CH₃ 605 isopropoxy 5823-(CH₃)₃C 606 3-CF₃-benzyl 583 4-F, 3-CH₃ 607 isopropylthio 584 3-Cl,4-Cl 608 cyclopentoxy 585 3,4-(CH₂)₄ 609 3-Cl-5-pyridinyloxy 5863-HCF₂CF₂O 610 3-CF₃S-benzyloxy 587 3-CHF₂O 611 3-CH₃, 4-CH₃-benzyloxy588 3-(CH₃)₂N 612 2-F, 3-CF₃-benzyloxy 589 3-cyclopropyl 613 3-F,5-CF₃-benzyloxy 590 3-(2-furyl) 614 4-(CH₃)₂CH-benzyloxy 591 3-CF₃CF₂615 1-phenylethoxy 592 4-NH₂ 616 4-F, 3-CH₃-benzoyl 593 3-CH₃, 4-CH₃,5-CH₃ 617 3-CF₃-phenyl 594 4-CH₃CH₂CH₂O 618 4-CH₃O-phenylamino 595 3-CF₃619 cyclopropoxy 596 2-NO₂ 620 4-NO₂-phenylthio

Calculated Observed Ex. Mass Mass No. R_(SUB1) [M + H]⁺ [M + H]⁺ 621 4-F522.1315 522.1297 622 2-Cl, 3-Cl 572.0630 572.0653 623 2-F, 5-Br600.0420 600.0404 624 4-Cl, 3-CH₃ 551.1098 551.1101 625 3-CH₃, 5-CH₃532.1722 532.1705 626 3-(CH₃)₃C 560.2035 560.2055 627 4-F, 3-CH₃536.1471 536.1480 628 3-Cl, 4-Cl 572.0630 572.0630 629 3,4-(CH₂)₄558.1879 558.1881 630 3-HCF₂CF₂O 631 3-CHF₂O 632 3-(CH₃)₂N 547.1831547.1844 633 3-cyclopropyl 634 3-(2-furyl) 635 3-CF₃CF₂ 6363-cyclopentyl 637 4-NH₂ 519.1519 519.1529 638 3-CH₃, 4-CH₃, 5-CH₃546.1879 546.1901 639 4-CH₃CH₂O 547.1594 547.1594 610 3-CF₃ 641 2-NO₂549.1260 549.1235 642 3,4-dimethyl 531.1644 531.1649 643 3-methyl,5-ethyl 546.1879 546.1899 644 3-methyl 517.1488 517.1493 6452,3-difluoro 540.1221 540.1182 646 4-CF₃ 572.1282 572.1268 647 2-fluoro,3-CF₃ 590.1189 590.1184 648 2-fluoro, 4-CF₃ 590.1189 590.1155 6492-chloro, 4-fluoro 556.0925 556.0891 650 4-n-propyl 546.1879 546.1878651 3-chloro, 4-fluoro 556.0925 556.0932 652 2,4-difluoro 540.1221540.1194 653 3,5-difluoro 540.1221 540.1217 654 3,4-difluoro 540.1221540.1248 655 3-fluoro 522.1315 522.1337 656 2-chloro 538.1019 538.1021657 2-fluoro 522.1315 522.1310 658 2,5-difluoro 540.1221 540.1255 6594-chloro, 2-fluoro 556.0926 556.0954 660 2,4-dichloro 572.0630 572.0667661 2-fluoro, 3-CH₃ 662 4-chloro 537.0942 537.0944 663 4-isopropyl,3-methyl 560.2035 560.2035 664 2,3,4-trifluoro 558.1127 558.1161 6652,3,5-trifluoro 558.1127 558.1109 666 4-propoxy 562.1828 562.1803 6674-isopropyl 546.1879 546.1899 668 4-CF₃O— 588.1233 588.1241 669 4-butoxy576.1958 576.1969 670 3-methyl, 4-CH₃S— 564.1443 564.1476 671 4-nitro549.1260 549.1306 672 3-CF₃S— 673 4-chloro, 3-fluoro 556.0925 556.0933674 3,5-dimethoxy 564.1623 564.1617 675 4-bromo 582.0716 582.0473 6764-sec-butyl 560.2035 560.2051 677 3-fluoro-2-nitro 567.1166 567.1135 6783-methoxy 533.1437 533.1450 679 4-bromo-2-nitro 627.0366 627.0375 6804-cyano 529.1362 529.1364 681 4-CH₃S— 550.1209 550.1251 682 3,4-(CH═CH)₂554.1566 554.1578 683 4-CH₃CH₂NH— 547.1832 547.1819 684 4-propionyl560.1672 560.1694 685 3-phenyl 580.1723 580.1772 686 4-cyclopentyl572.2035 572.2029

Calculated Observed Ex. Mass Mass No. R_(SUB2) [M + H]⁺ [M + H]⁺ 6876-methyl-3-pyridinyloxy 518.1440 518.1452 688 5-chloro-3-pyridinyloxy539.0972 539.1002 689 3-pyridinyloxy 505.1362 505.1369 6902-methyl-3-pyridinyloxy 519.1518 519.1517 691 5-indolinyloxy 543.1519543.1630 692 4-fluoro-2-pyridinyloxy 523.1268 523.1243 6932-cyano-3-pyridinyloxy 530.1315 530.1300 694 5-bromo-2-pyridinyloxy583.0667 583.0405 695 3-CF₃-2-pyridinyloxy 573.1236 573.1205 6962-pyridinylmethyleneoxy 519.1519 519.1522 697 cyclohexylmethyleneoxy524.2036 524.2028 698 isopropoxy 470.1488 470.1565 699 cyclopentyloxy496.1723 496.1719 700 neo-pentoxy 498.1879 498.1845 7014-(methoxycarbonyl)-butoxy 542.1777 542.1827 702 trifluoromethoxy496.0971 496.0959 703 2-methylpropoxy 484.1723 484.1718 7042-methoxyethoxy 486.1515 486.1537 705 2-oxobutoxy 498.1515 498.1529 706cyclohexyloxy 510.1880 510.1910 707 (methoxycarbonyl)methoxy 500.1308500.1297 708 4-tetrahydropyranyloxy 512.1672 512.1631 709 1-phenylethoxy532.1723 532.1711 710 3-CF₃O-benzyloxy 602.1389 602.1380 7113-trifluoromethyl-benzyloxy 586.1440 586.1419 712 3,5-dimethyl-benzyloxy546.1879 546.1890 713 3-bromo-benzyloxy 596.0671 596.0641 7143-CF₃S-benzyloxy 618.1161 618.1151 715 3,4-dimethyl-benzyloxy 546.1879546.1881 716 3,5-difluoro-benzyloxy 554.1378 554.1390 7172-fluoro-3-CF₃-benzyloxy 604.1346 604.1329 718 benzyloxy 518.1566518.1578 719 3,5-(CF₃)₂-benzyloxy 654.1314 654.1308 7203-fluoro-5-CF₃-benzyloxy 604.1346 604.1309 721 4-CF₃O-benzyloxy 602.1389602.1383 722 3-chloro-benzyloxy 552.1176 552.1157 723 4-ethyl-benzyloxy546.1879 546.1862 724 3-methyl-benzyloxy 532.1723 532.1692 7252-fluoro-benzyloxy 536.1472 536.1465 726 2,3-difluoro-benzyloxy 554.1378554.1364 727 4-isopropyl-benzyloxy 560.2036 560.2020 7284-methyl-benzyloxy 532.1723 532.1729 729 4-bromo-benzyloxy 596.0671596.0669 730 4-CF₃-benzyloxy 586.1440 586.1400 731 4-fluoro-benzyloxy536.1472 536.1454 732 3-iodo-benzyloxy 644.0533 644.0517 7334-CF₃S-benzyloxy 618.1161 618.1165 734 4-CF₂HO-benzyloxy 584.1483584.1480 735 4-fluoro-3-CF₃-benzyloxy 604.1346 604.1336 7362,3,5-trifluoro-benzyloxy 572.1284 572.1276 737 4-chloro-benzyloxy552.1176 552.1188 738 2,5-difluoro-benzyloxy 554.1378 554.1350 7393-chloro-2-fluoro-benzyloxy 570.1082 570.1069 740 2,4-(CF₃)₂-benzyloxy654.1314 654.1321 741 3,5-dichloro-benzyloxy 586.1787 586.1378 7423-methoxy-benzyloxy 548.1672 548.1676 743 4-cyano-benzyloxy 543.1519543.1517 744 4-tert-butyl-benzyloxy 574.2192 574.2163 745 isopropylthio486.1338 486.1351 746 4-nitrophenylthio 565.1032 565.1034 7474-acetylphenylthio 562.1287 562.1261 748 (4-chloro-thien-2-yl)- 574.0512574.0523 methylthio 749 4-methoxy-phenylamino 532.1597 532.1592 7503-methoxy-phenylamino 532.1597 532.1593 751 4-chloro-phenylamlno536.1102 536.1125 752 4-n-propyl-phenylamino 544.1961 544.1959 7533-cyano-phenylamino 527.1444 527.1448 754 3-CF₃-benzyl 570.1413 570.1480755 3-methyl-4-fluoro-benzyl 534.1679 534.1688 756 3-CF₃-phenyl 556.1334556.1339 757 2,4-dichloro-phenyl 556.0681 556.0651 758 3-methoxybenzyl532.1723 532.1705 759 4-methoxyphenyl 518.1566 518.1533 7603-chloro-4-fluoro-phenyl 540.0976 540.0957 761 4-fluoro-3-methyl-benzoyl548.1410 548.1441 762 3-chlorobenzyl 536.1227 536.1218 7633,4-dimethylbenzyl 530.1930 530.1887 764 3,5-dichlorobenzyl 570.0838570.0801 765 2,3,4-trifluorophenyl 542.1177 542.1152 7663-chloro-4-fluoro-benzyl 554.1133 554.1108 767 4-fluoro-3-methyl-phenyl520.1523 520.1494 768 3-methyl-4-chloro-benzyl 550.1384 550.1380 7692-methylpropanoyl 482.1566 482.1576 770 4-methylthiobenzyl 548.1494548.1503 771 4-fluorophenyl 506.1366 506.1336 772 4-chlorophenyl522.1071 522.1049 773 3-methoxyphenyl 518.1566 518.1544 7744-methylbenzyl 516.1774 516.1769 775 1-hydroxy-2-methyl-propyl 484.1723484.1725 776 benzyl 502.1617 502.1609 777 2-CF₃-phenyl 556.1334 556.1286778 3,4-dichlorophenyl 556.0681 556.0698 779 benzoyl 516.1410 516.1383780 4-fluorobenzoyl 534.1315 534.1273 781 N-piperidinyl 494.1804494.1804 782 phenyl 488.1460 488.1457 783 thien-2-yl 494.1024 494.0987

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H]⁺ [M +H]⁺ 784 phenoxy 3-cyclopentyl 456.2150 456.2143 785 phenoxy 3-isopropoxy446.1943 446.1936 786 phenoxy 3-CF₃S 488.1119 488.1116 787 4-F-phenoxy3-CF₃S 505.0946 505.0927 788 4-F-phenoxy 3-sec-butoxy 478.2005 478.1880789 phenoxy 3-(CF₃)₂COH— 554.1378 554.1385 790 4-CH₃- 3-CF₃S 502.1275502.1261 phenoxy 791 phenoxy 3-(2-furyl) 454.1630 454.1635 7924-F-phenoxy 3-isopropoxy 464.1849 464.1867 793 phenoxy 3-isobutyl444.2150 444.2157 794 phenoxy 3-tert-butoxy 460.2100 460.2103 7954-F-phenoxy 3-CH₃CH₂O— 450.1692 450.1682 796 4-F-phenoxy 3-CF₃O—490.1253 490.1211 797 phenoxy 4-F-3-(2-furyl)- 472.1536 472.1530 7984-F-phenoxy 3-n-propoxy- 464.1849 464.1820 799 4-F-phenoxy3-cyclopentyloxy- 490.2005 490.1998 800 phenoxy 3-(3-furyl)- 454.1630454.1646 801 4-F-phenoxy 3-cyclopropyl- 476.1849 476.1857 methyleneoxy802 phenoxy 3-CF₃CH₂O— 486.1504 486.1498

Example Table 9.(3R)-[N-(aryl)-[(aryl)methyl]amino]-1,1,1,2,2-pentafluoro-3-butanols

[0433]

Ex. No. R_(SUB1) 803 3-isopropyl 804 2-Cl, 3-Cl 805 3-CF₃O 806 4-F 8074-CH₃ 808 2-F, 5-Br 809 4-Cl, 3-CH₃CH₂ 810 3-CH₃CH₂ 811 3-CH₃, 5-CH₃ 8123-(CH₃)₃C 813 4-F, 3-CH₃ 814 3-Cl, 4-Cl 815 3,4-(CH₂)₄ 816 3-HCF₂CF₂O817 3-CHF₂O 818 3-(CH₃)₂N 819 3-cyclopropyl 820 3-(2-furyl) 821 3-CF₃CF₂822 4-NH₂ 823 3-CH₃, 4-CH₃, 5-CH₃ 824 4-CH₃CH₂CH₂O 825 3-CF₃ 826 2-NO₂

Ex. No. R_(SUB2) 827 3-CF₃O-benzyloxy 828 3-CF₃-benzyloxy 829 3-F,5-F-benzyloxy 830 cyclohexylmethyleneoxy 831 benzyloxy 832 3-CF₃,5-CF₃-benzyloxy 833 4-CF₃O-benzyloxy 834 4-CH₃CH₂-benzyloxy 835isopropoxy 836 3-CF₃-benzyl 837 isopropylthio 838 cyclopentoxy 8393-Cl-5-pyridinyloxy 840 3-CF₃S-benzyloxy 841 3-CH₃, 4-CH₃-benzyloxy 8422-F, 3-CF₃-benzyloxy 843 3-F, 5-CF₃-benzyloxy 844 4-(CH₃)₂CH-benzyloxy845 1-phenylethoxy 846 4-F, 3-CH₃-benzoyl 847 3-CF₃-phenyl 8484-CH₃O-phenylamino 849 cyclopropoxy 850 4-NO₂-phenylthio

Ex. No. R_(SUB1) 851 3-isopropyl 852 2-Cl, 3-Cl 853 3-CF₃O 854 4-F 8554-CH₃ 856 2-F, 5-Br 857 4-Cl, 3-CH₃CH₂ 858 3-CH₃CH₂ 859 3-CH₃, 5-CH₃ 8603-(CH₃)₃C 861 4-F, 3-CH₃ 862 3-Cl, 4-Cl 863 3,4-(CH₂)₄ 864 3-HCF₂CF₂O865 3-CHF₂O 866 3-(CH₃)₂N 867 3-cyclopropyl 868 3-(2-furyl) 869 3-CF₃CF₂870 4-NH₂ 871 3-CH₃, 4-CH₃, 5-CH₃ 872 4-CH₃CH₂CH₂O 873 3-CF₃ 874 2-NO₂

Ex. No. R_(SUB2) 875 3-CF₃O-benzyloxy 876 3-CF₃-benzyloxy 877 3-F,5-F-benzyloxy 878 cyclohexylmethyleneoxy 879 benzyloxy 880 3-CF₃,5-CF₃-benzyloxy 881 4-CF₃O-benzyloxy 882 4-CH₃CH₂-benzyloxy 883isopropoxy 884 3-CF₃-benzyl 885 isopropylthio 886 cyclopentoxy 8873-Cl-5-pyridinyloxy 888 3-CF₃S-benzyloxy 889 3-CH₃, 4-CH₃-benzyloxy 8902-F, 3-CF₃-benzyloxy 891 3-F, 5-CF₃-benzyloxy 892 4-(CH₃)₂CH-benzyloxy893 1-phenylethoxy 894 4-F, 3-CH₃-benzoyl 895 3-CF₃-phenyl 8964-CH₃O-phenylamino 897 cyclopropoxy 898 4-NO₂-phenylthio

Example Table 10. Substituted(2R)-3-[N-(aryl)-[(aryl)oxy]amino]-1,1,1-trifluoro-2-propanols

[0434]

Ex. No. R_(SUB1) 899 3-isopropyl 900 2-Cl, 3-Cl 901 3-CF₃O 902 4-F 9034-CH₃ 904 2-F, 5-Br 905 4-Cl, 3-CH₃CH₂ 906 3-CH₃CH₂ 907 3-CH₃, 5-CH₃ 9083-(CH₃)₃C 909 4-F, 3-CH₃ 910 3-Cl, 4-Cl 911 3,4-(CH₂)₄ 912 3-HCF₂CF₂O913 3-CHF₂O 914 3-(CH₃)₂N 915 3-cyclopropyl 916 3-(2-furyl) 917 3-CF₃CF₂918 4-NH₂ 919 3-CH₃, 4-CH₃, 5-CH₃ 920 4-CH₃CH₂CH₂O 921 3-CF₃ 922 2-NO₂

Ex. No. R_(SUB2) 923 3-CF₃O-benzyloxy 924 3-CF₃-benzyloxy 925 3-F,5-F-benzyloxy 926 cyclohexylmethyleneoxy 927 benzyloxy 928 3-CF₃,5-CF₃-benzyloxy 929 4-CF₃O-benzyloxy 930 4-CH₃CH₂-benzyloxy 931isopropoxy 932 3-CF₃-benzyl 933 isopropylthio 934 cyclopentoxy 9353-Cl-5-pyridinyloxy 936 3-CF₃S-benzyloxy 937 3-CH₃, 4-CH₃-benzyloxy 9382-F, 3-CF₃-benzyloxy 939 3-F, 5-CF₃-benzyloxy 940 4-(CH₃)₂CH-benzyloxy941 1-phenylethoxy 942 4-F, 3-CH₃-benzoyl 943 3-CF₃-phenyl 9444-CH₃O-phenylamino 945 cyclopropoxy 946 4-NO₂-phenylthio

Ex. No. R_(SUB1) 947 3-isopropyl 948 2-Cl, 3-Cl 949 3-CF₃O 950 4-F 9514-CH₃ 952 2-F, 5-Br 953 4-Cl, 3-CH₃CH₂ 954 3-CH₃CH₂ 955 3-CH₃, 5-CH₃ 9563-(CH₃)₃C 957 4-F, 3-CH₃ 958 3-Cl, 4-Cl 959 3,4-(CH₂)₄ 960 3-HCF₂CF₂O961 3-CHF₂O 962 3-(CH₃)₂N 963 3-cyclopropyl 964 3-(2-furyl) 965 3-CF₃CF₂966 4-NH₂ 967 3-CH₃, 4-CH₃, 5-CH₃ 968 4-CH₃CH₂CH₂O 969 3-CF₃ 970 2-NO₂

Ex. No. R_(SUB2) 971 3-CF₃O-benzyloxy 972 3-CF₃-benzyloxy 973 3-F,5-F-benzyloxy 974 cyclohexylmethyleneoxy 975 benzyloxy 976 3-CF₃,5-CF₃-benzyloxy 977 4-CF₃O-benzyloxy 978 4-CH₃CH₂-benzyloxy 979isopropoxy 980 3-CF₃-benzyl 981 isopropylthio 982 cyclopentoxy 9833-Cl-5-pyridinyloxy 984 3-CF₃S-benzyloxy 985 3-CH₃, 4-CH₃-benzyloxy 9862-F, 3-CF₃-benzyloxy 987 3-F, 5-CF₃-benzyloxy 988 4-(CH₃)₂CH-benzyloxy989 1-phenylethoxy 990 4-F, 3-CH₃-benzoyl 991 3-CF₃-phenyl 9924-CH₃O-phenylamino 993 cyclopropoxy 994 4-NO₂-phenylthio

Ex. No. R_(SUB1) 995 3-isopropyl 996 2-Cl, 3-Cl 997 3-CF₃O 998 4-F 9994-CH₃ 1000 2-F, 5-Br 1001 4-Cl, 3-CH₃CH₂ 1002 3-CH₃CH₂ 1003 3-CH₃, 5-CH₃1004 3-(CH₃)₃C 1005 4-F, 3-CH₃ 1006 3-Cl, 4-Cl 1007 3,4-(CH₂)₄ 10083-HCF₂CF₂O 1009 3-CHF₂O 1010 3-(CH₃)₂N 1011 3-cyclopropyl 10123-(2-furyl) 1013 3-CF₃CF₂ 1014 4-NH₂ 1015 3-CH₃, 4-CH₃, 5-CH₃ 10164-CH₃CH₂CH₂O 1017 3-CF₃ 1018 2-NO₂

Ex. No. R_(SUB2) 1019 3-CF₃O-benzyloxy 1020 3-CF₃-benzyloxy 1021 3-F,5-F-benzyloxy 1022 cyclohexylmethyleneoxy 1023 benzyloxy 1024 3-CF₃,5-CF₃-benzyloxy 1025 4-CF₃O-benzyloxy 1026 4-CH₃CH₂-benzyloxy 1027isopropoxy 1028 3-CF₃-benzyl 1029 isopropylthio 1030 cyclopentoxy 10313-Cl-5-pyridinyloxy 1032 3-CF₃S-benzyloxy 1033 3-CH₃, 4-CH₃-benzyloxy1034 2-F, 3-CF₃-benzyloxy 1035 3-F, 5-CF₃-benzyloxy 10364-(CH₃)₂CH-benzyloxy 1037 1-phenylethoxy 1038 4-F, 3-CH₃-benzoyl 10393-CF₃-phenyl 1040 4-CH₃O-phenylamino 1041 cyclopropoxy 10424-NO₂-phenylthio

Ex. No. R_(SUB1) 1043 3-isopropyl 1044 2-Cl, 3-Cl 1045 3-CF₃O 1046 4-F1047 4-CH₃ 1048 2-F, 5-Br 1049 4-Cl, 3-CH₃CH₂ 1050 3-CH₃CH₂ 1051 3-CH₃,5-CH₃ 1052 3-(CH₃)₃C 1053 4-F, 3-CH₃ 1054 3-Cl, 4-Cl 1055 3,4-(CH₂)₄1056 3-HCF₂CF₂O 1057 3-CHF₂O 1058 3-(CH₃)₂N 1059 3-cyclopropyl 10603-(2-furyl) 1061 3-CF₃CF₂ 1062 4-NH₂ 1063 3-CH₃, 4-CH₃, 5-CH₃ 10644-CH₃CH₂CH₂O 1065 3-CF₃ 1066 2-NO₂

Ex. No. R_(SUB2) 1067 3-CF₃O-benzyloxy 1068 3-CF₃-benzyloxy 1069 3-F,5-F-benzyloxy 1070 cyclohexylmethyleneoxy 1071 benzyloxy 1072 3-CF₃,5-CF₃-benzyloxy 1073 4-CF₃O-benzyloxy 1074 4-CH₃CH₂-benzyloxy 1075isopropoxy 1076 3-CF₃-benzyl 1077 isopropylthio 1078 cyclopentoxy 10793-Cl-5-pyridinyloxy 1080 3-CF₃S-benzyloxy 1081 3-CH₃, 4-CH₃-benzyloxy1082 2-F, 3-CF₃-benzyloxy 1083 3-F, 5-CF₃-benzyloxy 10844-(CH₃)₂CH-benzyloxy 1085 1-phenylethoxy 1086 4-F, 3-CH₃-benzoyl 10873-CF₃-phenyl 1088 4-CH₃O-phenylamino 1089 cyclopropoxy 10904-NO₂-phenylthio

Ex. No. R_(SUB1) 1091 3-isopropyl 1092 2-Cl, 3-Cl 1093 3-CF₃O 1094 4-F1095 4-CH₃ 1096 2-F, 5-Br 1097 4-Cl, 3-CH₃CH₂ 1098 3-CH₃CH₂ 1099 3-CH₃,5-CH₃ 1100 3-(CH₃)₃C 1101 4-F, 3-CH₃ 1102 3-Cl, 4-Cl 1103 3,4-(CH₂)₄1104 3-HCF₂CF₂O 1105 3-CHF₂O 1106 3-(CH₃)₂N 1107 3-cyclopropyl 11083-(2-furyl) 1109 3-CF₃CF₂ 1110 4-NH₂ 1111 3-CH₃, 4-CH₃, 5-CH₃ 11124-CH₃CH₂CH₂O 1113 3-CF₃ 1114 2-NO₂

Ex. No. R_(SUB2) 1115 3-CF₃O-benzyloxy 1116 3-CF₃-benzyloxy 1117 3-F,5-F-benzyloxy 1118 cyclohexylmethyleneoxy 1119 benzyloxy 1120 3-CF₃,5-CF₃-benzyloxy 1121 4-CF₃O-benzyloxy 1122 4-CH₃CH₂-benzyloxy 1123isopropoxy 1124 3-CF₃-benzyl 1125 isopropylthio 1126 cyclopentoxy 11273-Cl-5-pyridinyloxy 1128 3-CF₃S-benzyloxy 1129 3-CH₃, 4-CH₃-benzyloxy1130 2-F, 3-CF₃-benzyloxy 1131 3-F, 5-CF₃-benzyloxy 11324-(CH₃)₂CH-benzyloxy 1133 1-phenylethoxy 1134 4-F, 3-CH₃-benzoyl 11353-CF₃-phenyl 1136 4-CH₃O-phenylamino 1137 cyclopropoxy 11384-NO₂-phenylthio

Example Table 11.(2R)-3-[N-(aryl)-[(aryl)methyl]amino]-1,1-difluoro-1-chloro-2-propanols

[0435]

Ex. No. R_(SUB1) 1139 3-isopropyl 1140 2-Cl, 3-Cl 1141 3-CF₃O 1142 4-F1143 4-CH₃ 1144 2-F, 5-Br 1145 4-Cl, 3-CH₃CH₂ 1146 3-CH₃CH₂ 1147 3-CH₃,5-CH₃ 1148 3-(CH₃)₃C 1149 4-F, 3-CH₃ 1150 3-Cl, 4-Cl 1151 3,4-(CH₂)₄1152 3-HCF₂CF₂O 1153 3-CHF₂O 1154 3-(CH₃)₂N 1155 3-cyclopropyl 11563-(2-furyl) 1157 3-CF₃CF₂ 1158 4-NH₂ 1159 3-CH₃, 4-CH₃, 5-CH₃ 11604-CH₃CH₂CH₂O 1161 3-CF₃ 1162 2-NO₂

Ex. No. R_(SUB2) 1163 3-CF₃O-benzyloxy 1164 3-CF₃-benzyloxy 1165 3-F,5-F-benzyloxy 1166 cyclohexylmethyleneoxy 1167 benzyloxy 1168 3-CF₃,5-CF₃-benzyloxy 1169 4-CF₃O-benzyloxy 1170 4-CH₃CH₂-benzyloxy 1171isopropoxy 1172 3-CF₃-benzyl 1173 isopropylthio 1174 cyclopentoxy 11753-Cl-5-pyridinyloxy 1176 3-CF₃S-benzyloxy 1177 3-CH₃, 4-CH₃-benzyloxy1178 2-F, 3-CF₃-benzyloxy 1179 3-F, 5-CF₃-benzyloxy 11804-(CH₃)₂CH-benzyloxy 1181 1-phenylethoxy 1182 4-F, 3-CH₃-benzoyl 11833-CF₃-phenyl 1184 4-CH₃O-phenylamino 1185 cyclopropoxy 11864-NO₂-phenylthio

Ex. No. R_(SUB1) 1187 3-isopropyl 1188 2-Cl, 3-Cl 1189 3-CF₃O 1190 4-F1191 4-CH₃ 1192 2-F, 5-Br 1193 4-Cl, 3-CH₃CH₂ 1194 3-CH₃CH₂ 1195 3-CH₃,5-CH₃ 1196 3-(CH₃)₃C 1197 4-F, 3-CH₃ 1198 3-Cl, 4-Cl 1199 3,4-(CH₂)₄1200 3-HCF₂CF₂O 1201 3-CHF₂O 1202 3-(CH₃)₂N 1203 3-cyclopropyl 12043-(2-furyl) 1205 3-CF₃CF₂ 1206 4-NH₂ 1207 3-CH₃, 4-CH₃, 5-CH₃ 12084-CH₃CH₂CH₂O 1209 3-CF₃ 1210 2-NO₂

Ex. No. R_(SUB2) 1211 3-CF₃O-benzyloxy 1212 3-CF₃-benzyloxy 1213 3-F,5-F-benzyloxy 1214 cyclohexylmethyleneoxy 1215 benzyloxy 1216 3-CF₃,5-CF₃-benzyloxy 1217 4-CF₃O-benzyloxy 1218 4-CH₃CH₂-benzyloxy 1219isopropoxy 1220 3-CF₃-benzyl 1221 isopropylthio 1222 cyclopentoxy 12233-Cl-5-pyridinyloxy 1224 3-CF₃S-benzyloxy 1225 3-CH₃, 4-CH₃-benzyloxy1226 2-F, 3-CF₃-benzyloxy 1227 3-F, 5-CF₃-benzyloxy 12284-(CH₃)₂CH-benzyloxy 1229 1-phenylethoxy 1230 4-F, 3-CH₃-benzoyl 12313-CF₃-phenyl 1232 4-CH₃O-phenylamino 1233 cyclopropoxy 12344-NO₂-phenylthio

Example Table 12. (2R)-3-[N,N′-(diaryl)amino]-1,1,1-trifluoro-2-propanols

[0436]

Ex. No. R_(SUB1) 1235 3-isopropyl 1236 2-Cl, 3-Cl 1237 3-CF₃O 1238 4-F1239 4-CH₃ 1240 2-F, 5-Br 1241 4-Cl, 3-CH₃CH₂ 1242 3-CH₃CH₂ 1243 3-CH₃,5-CH₃ 1244 3-(CH₃)₃C 1245 4-F, 3-CH₃ 1246 3-Cl, 4-Cl 1247 3,4-(CH₂)₄1248 3-HCF₂CF₂O 1249 3-CHF₂O 1250 3-(CH₃)₂N 1251 3-cyclopropyl 12523-(2-furyl) 1253 3-CF₃CF₂ 1254 4-NH₂ 1255 3-CH₃, 4-CH₃, 5-CH₃ 12564-CH₃CH₂CH₂O 1257 3-CF₃ 1258 2-NO₂

Ex. No. R_(SUB2) 1259 3-CF₃O-benzyloxy 1260 3-CF₃-benzyloxy 1261 3-F,5-F-benzyloxy 1262 cyclohexylmethyleneoxy 1263 benzyloxy 1264 3-CF₃,5-CF₃-benzyloxy 1265 4-CF₃O-benzyloxy 1266 4-CH₃CH₂-benzyloxy 1267isopropoxy 1268 3-CF₃-benzyl 1269 isopropylthio 1270 cyclopentoxy 12713-Cl-5-pyridinyloxy 1272 3-CF₃S-benzyloxy 1273 3-CH₃, 4-CH₃-benzyloxy1274 2-F, 3-CF₃-benzyloxy 1275 3-F, 5-CF₃-benzyloxy 12764-(CH₃)₂CH-benzyloxy 1277 1-phenylethoxy 1278 4-F, 3-CH₃-benzoyl 12793-CF₃-phenyl 1280 4-CH₃O-phenylamino 1281 cyclopropoxy 12824-NO₂-phenylthio

Ex. No. R_(SUB1) 1283 3-isopropyl 1284 2-Cl, 3-Cl 1285 3-CF₃O 1286 4-F1287 4-CH₃ 1288 2-F, 5-Br 1289 4-Cl, 3-CH₃CH₂ 1290 3-CH₃CH₂ 1291 3-CH₃,5-CH₃ 1292 3-(CH₃)₃C 1293 4-F, 3-CH₃ 1294 3-Cl, 4-Cl 1295 3,4-(CH₂)₄1296 3-HCF₂CF₂O 1297 3-CHF₂O 1298 3-(CH₃)₂N 1299 3-cyclopropyl 13003-(2-furyl) 1301 3-CF₃CF₂ 1302 4-NH₂ 1303 3-CH₃, 4-CH₃, 5-CH₃ 13044-CH₃CH₂CH₂O 1305 3-CF₃ 1306 2-NO₂

Ex. No. R_(SUB2) 1307 3-CF₃O-benzyloxy 1308 3-CF₃-benzyloxy 1309 3-F,5-F-benzyloxy 1310 cyclohexylmethyleneoxy 1311 benzyloxy 1312 3-CF₃,5-CF₃-benzyloxy 1313 4-CF₃O-benzyloxy 1314 4-CH₃CH₂-benzyloxy 1315isopropoxy 1316 3-CF₃-benzyl 1317 isopropylthio 1318 cyclopentoxy 13193-Cl-5-pyridinyloxy 1320 3-CF₃S-benzyloxy 1321 3-CH₃, 4-CH₃-benzyloxy1322 2-F, 3-CF₃-benzyloxy 1323 3-F, 5-CF₃-benzyloxy 13244-(CH₃)₂CH-benzyloxy 1325 1-phenylethoxy 1326 4-F, 3-CH₃-benzoyl 13273-CF₃-phenyl 1328 4-CH₃O-phenylamino 1329 cyclopropoxy 13304-NO₂-phenylthio

Ex. No. R_(SUB1) 1331 3-isopropyl 1332 2-Cl, 3-Cl 1333 3-CF₃O 1334 4-F1335 4-CH₃ 1336 2-F, 5-Br 1337 4-Cl, 3-CH₃CH₂ 1338 3-CH₃CH₂ 1339 3-CH₃,5-CH₃ 1340 3-(CH₃)₃C 1341 4-F, 3-CH₃ 1342 3-Cl, 4-Cl 1343 3,4-(CH₂)₄1344 3-HCF₂CF₂O 1345 3-CHF₂O 1346 3-(CH₃)₂N 1347 3-cyclopropyl 13483-(2-furyl) 1349 3-CF₃CF₂ 1350 4-NH₂ 1351 3-CH₃, 4-CH₃, 5-CH₃ 13524-CH₃CH₂CH₂O 1353 3-CF₃ 1354 2-NO₂

Ex. No. R_(SUB2) 1355 3-CF₃O-benzyloxy 1356 3-CF₃-benzyloxy 1357 3-F,5-F-benzyloxy 1358 cyclohexylmethyleneoxy 1359 benzyloxy 1360 3-CF₃,5-CF₃-benzyloxy 1361 4-CF₃O-benzyloxy 1362 4-CH₃CH₂-benzyloxy 1363isopropoxy 1364 3-CF₃-benzyl 1365 isopropylthio 1366 cyclopentoxy 13673-Cl-5-pyridinyloxy 1368 3-CF₃S-benzyloxy 1369 3-CH₃, 4-CH₃-benzyloxy1370 2-F, 3-CF₃-benzyloxy 1371 3-F, 5-CF₃-benzyloxy 13724-(CH₃)₂CH-benzyloxy 1373 1-phenylethoxy 1374 4-F, 3-CH₃-benzoyl 13753-CF₃-phenyl 1376 4-CH₃O-phenylamino 1377 cyclopropoxy 13784-NO₂-phenylthio

Ex. No. R_(SUB1) 1379 3-isopropyl 1380 2-Cl, 3-Cl 1381 3-CF₃O 1382 4-F1383 4-CH₃ 1384 2-F, 5-Br 1385 4-Cl, 3-CH₃CH₂ 1386 3-CH₃CH₂ 1387 3-CH₃,5-CH₃ 1388 3-(CH₃)₃C 1389 4-F, 3-CH₃ 1390 3-Cl, 4-Cl 1391 3,4-(CH₂)₄1392 3-HCF₂CF₂O 1393 3-CHF₂O 1394 3-(CH₃)₂N 1395 3-cyclopropyl 13963-(2-furyl) 1397 3-CF₃CF₂ 1398 4-NH₂ 1399 3-CH₃, 4-CH₃, 5-CH₃ 14004-CH₃CH₂CH₂O 1401 3-CF₃ 1402 2-NO₂

Ex. No. R_(SUB2) 1403 3-CF₃O-benzyloxy 1404 3-CF₃-benzyloxy 1405 3-F,5-F-benzyloxy 1406 cyclohexylmethyleneoxy 1407 benzyloxy 1408 3-CF₃,5-CF₃-benzyloxy 1409 4-CF₃O-benzyloxy 1410 4-CH₃CH₂-benzyloxy 1411isopropoxy 1412 3-CF₃-benzyl 1413 isopropylthio 1414 cyclopentoxy 14153-Cl-5-pyridinyloxy 1416 3-CF₃S-benzyloxy 1417 3-CH₃, 4-CH₃-benzyloxy1418 2-F, 3-CF₃-benzyloxy 1419 3-F, 5-CF₃-benzyloxy 14204-(CH₃)₂CH-benzyloxy 1421 1-phenylethoxy 1422 4-F, 3-CH₃-benzoyl 14233-CF₃-phenyl 1424 4-CH₃O-phenylamino 1425 cyclopropoxy 14264-NO₂-phenylthio

Bioassays CETP Activity In Vitro Assay of CETP Inhibition using PurifiedComponents (Reconstituted Buffer Assay)

[0437] The ability of compounds to inhibit CETP activity was assessedusing an in vitro assay that measured the rate of transfer ofradiolabeled cholesteryl ester ([³H]CE) from HDL donor particles to LDLacceptor particles. Details of the assay are provided by Glenn, K. C. etal. (Glenn and Melton, “Quantification of Cholesteryl Ester TransferProtein (CETP): A) CETP Activity and B) Immunochemical Assay of CETPProtein,” Meth. Enzymol., 263, 339-351 (1996)). Human recombinant CETPcan be obtained from the serum-free conditioned medium of CHO cellstransfected with a cDNA for CETP and purified as described by Wang, S.et al. (J. Biol. Chem. 267, 17487-17490 (1992)). To measure CETPactivity, [³H]CE-labeled-HDL, LDL, CETP and assay buffer (50 mMtris(hydroxymethyl)aminomethane, pH 7.4; 150 mM sodium chloride; 2 mMethylenediamine-tetraacetic acid (EDTA); 1% bovine serum albumin) wereincubated in a final volume of 200 μL, for 2 hours at 37° C. in 96 wellplates. Inhibitors were included in the assay by diluting from a 10 mMDMSO stock solution into 16% (v/v) aqueous DMSO so that the finalconcentration of inhibitor was 800 μM. The inhibitors were then diluted1:1 with CETP in assay buffer, and then 25 μL of that solution was mixedwith 175 μL of lipoprotein pool for assay. Following incubation, LDL wasdifferentially precipitated by the addition of 50 μL of 1% (w/v) dextransulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at roomtemperature for 10 minutes. A potion of the solution (200 μL) wastransferred to a filter plate (Millipore). After filtration, theradioactivity present in the precipitated LDL was measured by liquidscintillation counting. Correction for non-specific transfer orprecipitation was made by including samples that do not contain CETP.The rate of [³H]CE transfer using this assay was linear with respect totime and CETP concentration, up to 25-30% of [3H]CE transferred.

[0438] The potency of test compounds was determined by performing theabove described assay in the presence of varying concentrations of thetest compounds and determining the concentration required for 50%inhibition of transfer of [³H]CE from HDL to LDL. This value was definedas the IC₅₀. The IC₅₀ values determined from this assay are accuratewhen the IC₅₀ is greater than 10 nM. In the case where compounds havegreater inhibitory potency, accurate measurements of IC₅₀ may bedetermined using longer incubation times (up to 18 hours) and lowerfinal concentrations of CETP (<50 nM).

[0439] Examples of IC₅₀ values determined by these methods aresummarized in Table 9.

Assay of CETP Inhibition in Human Plasma

[0440] Blood was obtained from healthy volunteers, recruited from thepersonnel of Monsanto Company, Saint Louis, Mo. Blood was collected intubes containing EDTA (EDTA plasma pool). The EDTA human plasma pool,previously stored at −20° C., was thawed at room temperature andcentrifuged for minutes to remove any particulate matter. Tritiated HDL,radiolabeled in the cholesteryl ester moiety ([³H]CE-HDL) as describedby Morton and Zilversmit (J. Biol. Chem., 256, 11992-95 (1981)), wasadded to the plasma to a final concentration of 25 μg/mL cholesterol.Equal volumes (396 μL) of the plasma containing the [³H]CE-HDL wereadded by pipette into micro tubes (Titertube®, Bio-Rad laboratories,Hercules, Calif.). Inhibitor compounds, dissolved as 20-50 mM stocksolutions in DMSO, were serially diluted in DMSO (or an alternativesolvent in some cases, such as dimethylformamide or ethanol). Four μL ofeach of the serial dilutions of inhibitor compounds or DMSO alone werethen added to each of the tubes containing plasma (396 μL). Aftermixing, triplicate aliquots (100 μL) from each plasma tube were thentransferred to wells of 96-well round-bottomed polystyrene microtiterplates (Corning, Corning, N.Y.). Plates were sealed with plastic filmand incubated at 37° C. for 4 hours. “Test” samples contained plasmawith dilutions of inhibitor compounds. “Control” samples containedplasma with DMSO diluted to the same concentration as the test samples,but without inhibitor. “Blank” samples were prepared as “control”samples, but were left in the micro tubes at 4° C. for the 4 hourincubation and were then added to the microtiter wells at the end of theincubation period. VLDL and LDL were precipitated by the addition of 10μL of precipitating reagent (1% (w/v) dextran sulfate (Dextralip50)/0.5M magnesium chloride, pH 7.4) to all wells. The wells were mixed on aplate mixer and then incubated at ambient temperature for 10 min. Theplates were then centrifuged at 1000×g for 30 min at 10° C. Thesupernatants (50 μL) from each well were then transferred to Picoplate™96 plate wells (Packard, Meriden, Conn.) containing Microscint™-40(Packard, Meriden, Conn.). The plates were heat-sealed (TopSeal™-P,Packard, Meriden, Conn.) according to the manufacturer's directions andmixed for 30 min. Radioactivity was measured on a microplatescintillation counter (TopCount, Packard, Meriden, Conn.). The maximumpercentage transfer in the control wells (% transfer) was determinedusing the following equation:${\% \quad {Transfer}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{control}} \right\rbrack \times 100}{{dpm}_{blank}}$

[0441] The percentage of transfer relative to the control (% control)was determined in the wells containing inhibitor compounds wasdetermined as follows:${\% \quad {Control}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{test}} \right\rbrack \times 100}{{dpm}_{blank} - {dpm}_{control}}$

[0442] IC₅₀ values were then calculated from plots of % control versusconcentration of inhibitor compound. IC₅₀ values were determined as theconcentration of inhibitor compound inhibiting transfer of [³H]CE fromthe supernatant [³H]CE-HDL to the precipitated VLDL and LDL by 50%compared to the transfer obtained in the control wells.

[0443] Examples of plasma IC₅₀ values determined by these methods aresummarized in Table 10.

Assay of CETP Inhibition in vivo

[0444] Inhibition of CETP activity by a test compound can be determinedby administering the compound to an animal by intravenous injection ororal gavage, measuring the amount of transfer of tritium-labeledcholesteryl ester ([³H]CE) from HDL to VLDL and LDL particles, andcomparing this amount of transfer with the amount of transfer observedin control animals.

[0445] Male golden Syrian hamsters were maintained on a diet of chowcontaining 0.24% cholesterol for at least two weeks prior to the study.For animals receiving intravenous dosing immediately before theexperiment, animals were anesthetized with pentobarbital. Anesthesia wasmaintained throughout the experiment. In-dwelling catheters wereinserted into the jugular vein and carotid artery. At the start of theexperiment all animals received 0.2 mL of a solution containing[³H]CE-HDL into the jugular vein. [³H]CE-HDL is a preparation of humanHDL containing tritium-labeled cholesteryl ester, and was preparedaccording to the method of Glenn et al. (Meth. Enzymol., 263, 339-351(1996)). Test compound was dissolved as a 80 mM stock solution invehicle (2% ethanol: 98% PEG 400, Sigma Chemical Company, St. Louis,Mo., USA) and administered either by bolus injection or by continuousinfusion. Two minutes after the [³H]CE-HDL dose was administered,animals received 0.1 mL of the test solution injected into the jugularvein. Control animals received 0.1 mL of the intravenous vehiclesolution without test compound. After 5 minutes, the first blood samples(0.5 mL) were taken from the carotid artery and collected in standardmicrotainer tubes containing ethylenediamine tetraacetic acid. Saline(0.5 mL) was injected to flush the catheter and replace blood volume.Subsequent blood samples were taken at two hours and four hours by thesame method. Blood samples were mixed well and kept on ice until thecompletion of the experiment. Plasma was obtained by centrifugation ofthe blood samples at 4° C. The plasma (50 μL) was treated with 5 μL ofprecipitating reagent (dextran sulfate, 10 g/L; 0.5 M magnesiumchloride) to remove VLDL/LDL. After centrifugation, the resultingsupernatant (25 μL) containing the HDL was analyzed for radioactivityusing a liquid scintillation counter.

[0446] The percentage [³H]CE transferred from HDL to LDL and VLDL (%transfer) was calculated based on the total radioactivity in equivalentplasma samples before precipitation. Typically, the amount of transferfrom HDL to LDL and VLDL in control animals was 20% to 35% after 4hours. The polyethylene glycol vehicle was determined to have no effecton CETP activity in this model.

[0447] Alternatively, conscious, non-anesthetized animals received anoral gavage dose of test compound as a suspension in 0. 1% methylcellulose in water. At a time determined for each compound at whichplasma levels of the test substance reached their peak (C_(max)) afteroral dosing, the animals were anesthetized with pentobarbital and thendosed with 0.2 mL of a solution containing [³H]CE-HDL into the jugularvein as described above. Control animals received 0.25 mL of the vehiclesolution without test compound by oral gavage. After 4 hours, theanimals were sacrificed, blood samples were collected, and thepercentage [³H]CE transferred from HDL to LDL and VLDL (% transfer)assayed, as described above. The aqueous methyl cellulose vehicle wasdetermined to have no effect on CETP activity in this model. Resultsfrom testing in this model are summarized in Table 11.

[0448] Alternatively, inhibition of CETP activity by a test compound wasdetermined by administering the compound to mice which have beenselected for expression of human CETP (hCETP) by transgenic manipulation(hCETP mice). Test compounds were administered by intravenous injection,or oral gavage and the amount of transfer of tritium-labeled cholesterylester ([³H]CE) from HDL to VLDL and LDL particles was determined, andcompared to the amount of transfer observed in control animals. C57B1/6mice that were homozygous for the hCETP gene were maintained on a highfat chow diet, such as TD 88051, as described by Nishina et al. (J LipidRes., 31, 859-869 (1990)) for at least two weeks prior to the study.Mice received an oral gavage dose of test compound as a suspension in0.1% methyl cellulose in water or an intravenous bolus injection of testcompound in 10% ethanol and 90% polyethylene glycol. Control animalsreceived the vehicle solution without test compound by oral gavage or byan intravenous bolus injection. At the start of the experiment allanimals received 0.05 mL of a solution containing [³H]CE-HDL into thetail vein. [³H]CE-HDL is a preparation of human HDL containingtritium-labeled cholesteryl ester, and was prepared according to themethod of Glenn et al. (Meth. Enzymol., 263, 339-351 (1996)). After 30minutes, the animals were exsanguinated and blood collected in standardmicrotainer tubes containing ethylenediamine tetraacetic acid. Bloodsamples were mixed well and kept on ice until the completion of theexperiment. Plasma was obtained by centrifugation of the blood samplesat 4 ° C. The plasma was separated and analyzed by gel filtrationchromatography and the relative proportion of [3H]CE in the VLDL, LDLand HDL regions was determined.

[0449] The percentage [³H]CE transferred from HDL to LDL and VLDL (%transfer) was calculated based on the total radioactivity in equivalentplasma samples before precipitation. Typically, the amount of transferfrom HDL to LDL and VLDL in control animals was 20% to 35% after 30 min.The polyethylene glycol and the aqueous methyl cellulose vehicles weredetermined to have no effect on CETP activity in this model. Resultsfrom testing in this model are summarized in Table 12.

Assay of Plasma HDL Elevation in vivo

[0450] Syrian Golden hamsters were made hypercholesterolemic by feedingcholesterol supplemented chow for a minimum of two weeks, as describedabove. Test compounds were administered orally in selected aqueous oroil based vehicles for up to 1 week. Serum was obtained and analyzed byprecipitation or size exclusion chromatography for the relativeabundance of VLDL, LDL and HDL. Results from testing in this model aresummarized in Table 13.

[0451] Alternatively, a strain of C57b1 mouse was made to transgenicalyexpress human CETP. Plasma concentrations of hCETP ranged from 2-20μg/ml. The hCETP mice were made hypercholesterolemic by feedingcholesterol and fat supplemented chow for a minimum of two weeks, asdescribed above. Test compounds were administered orally in selectedaqueous or oil based vehicles for up to 1 week. Serum was obtained andanalyzed by size exclusion chromatography for the relative abundance ofVLDL, LDL and HDL. Results from testing in this model are summarized inTable 14.

[0452] Alternatively, cynomologous monkeys were maintained on a normalchow diet. The compound corresponding to example 8 was dissolved in acorn oil based vehicle and administered by oral gavage at 10 mpk q.d.for up to 11 days. Plasma levels of drug were detected throughout theexperiment in treated animals at ranges of 0.1-1.5 μg/mL. Periodically,plasma samples were taken and analyzed for total cholesterol and HDL.After seven days, the treated animals exhibited a 2% increase in HDL anda 5% increase in total cholesterol, relative to vehicle-treatedcontrols.

[0453] Alternatively, rabbits were maintained on a normal chow diet. Thecompound corresponding to example 8 was dissolved in a vehicle ofethanol:propylene glycol (1.5:18) and administered by Alzet pump at 30mg/day/animal for up to 14 days. Plasma concentrations of drug weredetected throughout the duration of the pump infusion in treated animalsand averaged 1.2 μg/mL. Periodically, plasma samples were taken andanalyzed for triglycerides, total cholesterol, and HDL. After fourteendays, the treated animals exhibited a 12% decrease in HDL, a 19%decrease in total cholesterol, as well as a 17% increase intriglycerides, compared to pre-dose levels. TABLE 9 Inhibition of CETPActivity by Examples in Reconstituted Buffer Assay. Ex. IC₅₀ No. (μM)  80.0008 11 0.001 19 0.004  9 0.008 10 0.012  2 0.014  4 0.014 20 0.027 220.027 12 0.034 14 0.04 18 0.044 16 0.049 43 0.058 23 0.066 34 0.076 410.086 21 0.11 13 0.13  1 0.14 33 0.15 38 0.18 36 0.20 37 0.21 40 0.23 350.28 24 0.33 42 0.38 27 0.44 26 0.53 29 0.72  3 0.76 28 0.86 32 1.2 251.4 39 1.6 15 1.6 30 2.7 33B 3.2  5 3.4 31 3.5  7 4.9 44 6.8 17 18  6 6844A >50

[0454] TABLE 10 Inhibition of CETP Activity by Examples in Human PlasmaAssay Ex. IC₅₀ No. (μM) 8 0.049 11 0.072 10 0.11 22 0.14 19 0.19 20 0.318 0.44 14 0.59 9 0.62 2 0.65 4 0.65 16 0.77 12 0.79 34 1.4 43 1.5 232.0 1 5.6 41 7.2 42 11 3 20

[0455] TABLE 11 Inhibition of CETP-mediated Transfer in Hamster Ex.Single Oral % Inhibition No. Dose of Transfer 8 10 mpk 35

[0456] TABLE 12 Inhibition of CETP-mediated Transfer in hCETP Mice. Ex.Single Oral % Inhibition No. Dose of Transfer 8 60 mpk 40

[0457] TABLE 13 Change in Lipoprotein Profile in Hamster. Oral Dose %Change in Ex. qd, Lipoprotein Profile No. 5 days HDL LDL VLDL 8 30 mpk12 −12 −22

[0458] TABLE 14 Change in Lipoprotein Profile in hCETP Mice. Oral Dose %Change in Ex. qd, Lipoprotein Profile No. 5 days HDL LDL VLDL 8 30 mpk12 20 —

What we claim is:
 1. A compound having the formula:

and a pharmaceutically-acceptable salt thereof, wherein; n is an integerselected from 1 through 4; X is oxy; R₁ is selected from the groupconsisting of haloalkyl, haloalkenyl, haloalkoxymethyl, andhaloalkenyloxymethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₁₆ is selected from the group consisting of hydrido, alkyl, acyl,aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the groupconsisting of a covalent single bond and a linear spacer moiety having achain length of 1 to 4 atoms linked to the point of bonding of anyaromatic substituent selected from the group consisting of R₄, R₈, R₉,and R₁₃ to form a heterocyclyl ring having from 5 through 10 contiguousmembers; D₁, D₂, J₁, J₂ and K₁ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that nomore than one of D₁, D₂, J₁, J₂ and K₁ is a covalent bond, no more thanone of D₁, D₂, J₁, J₂ and K₁ is O, no more than one of D₁, D₂, J₁ J₂ andK₁ is S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond when twoof D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁, D₂,J₁, J₂ and K₁ are N; D₃, D₄, J₃, J₄ and K₂ are independently selectedfrom the group consisting of C, N, O, S and covalent bond with theprovisos that no more than one is a covalent bond, no more than one ofD₃, D₄, J₃, J₄ and K2 is O, no more than one of D₃, D₄, J₃, J₄ and K₂ isS, no more than two of D₃, D₄, J₃, J₄ and K₂ are O and S, one of D₃, D₄,J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂are O and S, and no more than four of D₃, D₄, J₃, J₄and K₂are N; R₂ isselected from the group consisting of hydrido, aryl, aralkyl, alkyl,alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl,heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(A)Q; R₃ is selected from the group consisting of hydrido,hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl,alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl,dicyanoalkyl, carboxamide, and carboxamidoalkyl with the provisos that(CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelog stereochemical systemranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical systemranking than R₂; Y is selected from a group consisting of a covalentsingle bond, (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 and 2and (CH(R₁₄))_(g)—W—(CH(R₁₄))_(p) wherein g and p are integersindependently selected from 0 and 1; R₁₄ is selected from the groupconsisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy,alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy,carboxamide, carboxamidoalkyl; Z is selected from the group consistingof covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selectedfrom 1 and 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k areintegers independently selected from 0 and 1; W is selected from thegroup consisting of O, C(O), C(S), C(O)N(R₁₄), C(S)N(R₁₄), (R₁₄)NC(O),(R₁₄)NC(S), S, S(O), S(O)₂, S(O)₂N(R₁₄), (R₁₄)NS(O)₂, and N(R₁₄) withthe proviso that R₁₄ is other than cyano; R₁₅ is selected from the groupconsisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl,alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy,carboxamide, and carboxamidoalkyl; R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁,R₁₂, and R₁₃ are independently selected from the group consisting ofhydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino,acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl,aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl,aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that and R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are each independently selected to maintainthe tetravalent nature of carbon, trivalent nature of nitrogen, thedivalent nature of sulfur, and the divalent nature of oxygen; R₄ and R₅,R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂,and R₁₂ and R₁₃ are independently selected to form spacer pairs whereina spacer pair is taken together to form a linear moiety having from 3through 6 contiguous atoms connecting the points of bonding of saidspacer pair members to form a ring selected from the group consisting ofa cycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe provisos that no more than one of the group consisting of spacerpairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈, is used at thesame time and that no more than one of the group consisting of spacerpairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ is used atthe same time; R₄ and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ areindependently selected to form a spacer pair wherein said spacer pair istaken together to form a linear moiety wherein said linear moiety formsa ring selected from the group consisting of a partially saturatedheterocyclyl ring having from 5 through 8 contiguous members and aheteroaryl ring having from 5 through 6 contiguous members with theproviso that no more than one of the group consisting of spacer pairs R₄and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ is used at the same time.2. The compound as recited in claim 1 having the formula of:

or a pharmaceutically acceptable salt thereof, wherein; n is an integerselected from 1 through 3; X is oxy; R₁₆ is selected from the groupconsisting of hydrido and a spacer selected from the group consisting ofa covalent single bond and a linear spacer moiety having a chain lengthof 1 to 4 atoms linked to the point of bonding of any aromaticsubstituent selected from the group consisting of R₄, R₈, R₉, and R₁₃ toform a heterocyclyl ring having from 5 through 10 contiguous members; R₁is selected from the group consisting of haloalkyl and haloalkoxymethylwith the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than both R₂ and (CHR₃)_(n)—N(A)Q wherein A is Formula(II) and Q is Formula (III);

D₁, D₂, J₁, J₂ and K₁ are independently selected from the groupconsisting of C, N, O, S and a covalent bond with the provisos that nomore than one of D₁, D₂, J₁, J₂ and K₁ is a covalent bond, no more thanone of D₁, D₂, J₁, J₂ and K₁ is O, no more than one of D₁, D₂, J₁, J₂and K₁ is S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond whentwo of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁,D₂, J₁, J₂ and K₁ are N; D₃, D₄, J₃, J₄ and K₂ are independentlyselected from the group consisting of C, N, O, S and a covalent bondwith the provisos that no more than one of D₃, D₄, J₃, J₄ and K₂is acovalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ is O, no morethan one of D₃, D₄, J₃, J₄and K₂is S, one of D₃, D₄, J₃, J₄ and K₂mustbe a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and nomore than four of D₃, D₄, J₃, J₄ and K₂are N; R₂ is selected from thegroup consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl,haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, and heteroaryl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q; R₃is selected from the group consisting of hydrido, aryl, alkyl, alkenyl,haloalkyl, and haloalkoxyalkyl with the provisos that (CHR₃)_(n)—N(A)Qhas a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ anda higher Cahn-Ingold-Prelog stereochemical system ranking than R₂; Y isselected from the group consisting of a covalent single bond, (CH₂)_(q)wherein q is an integer selected from 1 and 2, and (CH₂)_(j)—O—(CH₂)_(k)wherein j and k are integers independently selected from 0 and 1; Y isselected from the group consisting of covalent single bond, (CH₂)_(q)wherein q is an integer selected from 1 and 2, and (CH₂)_(j)—O—(CH₂)_(k)wherein j and k are integers independently selected from 0 and 1; R₄,R₈, R₉, and R₁₃ are independently selected from the group consisting ofhydrido, halo, haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ areindependently selected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino,heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl,heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl; R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉and R₁₀, R₁₀ and R₁₁, R ₁₁ and R₁₂, and R₁₂ and R₁₃ are independentlyselected to form spacer pairs wherein a spacer pair is taken together toform a linear moiety having from 3 through 6 contiguous atoms connectingthe points of bonding of said spacer pair members to form a ringselected from the group consisting of a cycloalkenyl ring having 5through 8 contiguous members, a partially saturated heterocyclyl ringhaving 5 through 8 contiguous members, a heteroaryl ring having 5through 6 contiguous members, and an aryl with the provisos that no morethan one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆,R₆ and R₇, and R₇ and R₈, is used at the same time and that no more thanone of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ is used at the same time.
 3. The compound asrecited in claim 2 having the formula of:

or a pharmaceutically acceptable salt thereof, wherein; n is an integerselected from 1 through 3; R₁₆ is selected from the group consisting ofhydrido and a spacer selected from the group consisting of a covalentsingle bond and a linear spacer moiety having a chain length of 1 to 4atoms linked to the point of bonding of any aromatic substituentselected from the group consisting of R₄, R₈, R₉, and R₁₃ to form aheterocyclyl ring having from 5 through 10 contiguous members; R₁ isselected from the group consisting of haloalkyl and haloalkoxymethylwith the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than both R₂ and (CHR₃)_(n)−N(Ap)Qp wherein Ap is Formula(II-P) and Qp is Formula (III-P);

R₂ is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(Ap)Qp; R₃ is selected from the group consisting of hydrido,aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl with the provisosthat (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemicalsystem ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than R₂; Y is selected from the group consisting of acovalent single bond, (CH₂)_(q) wherein q is an integer selected from 1and 2, and (CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integersindependently selected from 0 and 1; Z is selected from the groupconsisting of covalent single bond, (CH₂)_(q) wherein q is an integerselected from 1 and 2, and (CH₂)_(j)—O—(CH₂)_(k) wherein j and k areintegers independently selected from 0 and 1; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido, halo,haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino,heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl,heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl; R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ are independentlyselected to form spacer pairs wherein a spacer pair is taken together toform a linear moiety having from 3 through 6 contiguous atoms connectingthe points of bonding of said spacer pair members to form a ringselected from the group consisting of a cycloalkenyl ring having 5through 8 contiguous members, a partially saturated heterocyclyl ringhaving 5 through 8 contiguous members, a heteroaryl ring having 5through 6 contiguous members, and an aryl with the provisos that no morethan one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆,R₆ and R₇, and R₇ and R₈, is used at the same time and that no more thanone of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ is used at the same time.
 4. The compound asrecited in claim 3 or a pharmaceutically acceptable salt thereof,wherein; n is the integer 1; R₁₆ is taken together with R₄, R₈, R₉, orR₁₃ to form a spacer selected from the group consisting of a covalentsingle bond, CH₂, CH(CH₃), CF₂, C(O), C(S), and SO₂; R₁ is selected fromthe group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂and (CHR₃)_(n)—N(Apc)Qp wherein Apc is Formula (II-PC) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, vinyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, and 2,2,3,3,3-pentafluoropropylwith the proviso that R₂ has a lower Cahn-Ingold-Prelog system rankingthan both R₁ and (CHR₃)_(n)—N(Apc)Qp; R₃ is selected from the groupconsisting of hydrido, methyl, ethyl, vinyl, phenyl,4-trifluoromethylphenyl, trifluoromethyl, trifluoromethoxymethyl,difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with theprovisos that (CHR₃)_(n)—N(Apc)Qp has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂; Y is selected from the groupconsisting of covalent single bond, oxy, methyleneoxy, methylene, andethylene; Z is selected from the group consisting of covalent singlebond, oxy, methyleneoxy, methylene, and ethylene; R₄, R₈, R₉, and R₁₃are independently selected from the group consisting of hydrido andfluoro; R₅ and R₁₀ are independently selected from the group consistingof 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy,4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy,4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy,chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl,3-chloro4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy,4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy,3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy,3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy,4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl,4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy,tert-butoxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio; R₆ and R₁₁ areindependently selected from the group consisting of chloro, fluoro,hydrido, difluoromethoxy, trifluoromethyl, trifluoromethoxy,pentafluoroethyl, and 1,1,2,2-tetrafluoroethoxy; R₇ and R₁₂ areindependently selected from the group consisting of hydrido, fluoro, andtrifluoromethyl.
 5. The compound as recited in claim 4 or apharmaceutically acceptable salt thereof, wherein: R₁₆ is taken togetherwith R₄, R₈, R₉, or R₁₃ to form a covalent single bond. n is the integer1; R₁ is selected from the group consisting of trifluoromethyl andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Apc)Qp wherein Apc is Formula (II-PC) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido and phenyl with theproviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than bothR₁ and (CHR₃)_(n)—N(Apc)Qp; R₃ is selected from the group consisting ofhydrido, methyl, trifluoromethyl, and difluoromethyl with the provisosthat (CHR₃)_(n)—N(Apc)Qp has a lower Cahn-Ingold-Prelog stereochemicalsystem ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than R₂; Y is methylene; Z is covalent single bond; R₄,R₈, R₉, and R₁₃ are independently selected from the group consisting ofhydrido and fluoro; R₅ is selected from the group consisting of5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy,3,4-dichlorophenoxy, 3difluoromethoxyphenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy,4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy,3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy,3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy,3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ isselected from the group consisting of cyclopentyl,1,1,2,2-tetrafluoroethoxy, 2-furyl,1,1-bis-trifluoromethyl-1-hydroxymethyl, isobutyl, isopropoxy,pentafluoroethyl, trifluoromethoxy, trifluoromethyl, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of fluoro and hydrido; R₇ and R₁₂ are independentlyselected from the group consisting of hydrido and fluoro.
 6. Thecompound as recited in claim 3 or a pharmaceutically acceptable saltthereof, wherein: n is an integer selected from 1 and 2; R₁ is selectedfrom the group consisting of haloalkyl and haloalkoxymethyl with theproviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical systemranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P)and Qp is Formula (III-P);

R₁₆ is hydrido; R₂ is selected from the group consisting of hydrido,aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl withthe proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking thanboth R₁ and (CHR₃)_(n)—N(Ap)Qp; R₃ is selected from the group consistingof hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl withthe provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂; Y is selected from the groupconsisting of a covalent single bond, oxy and C1-C2 alkylene; Z is acovalent single bond; R₄, R₈, R₉, and R₁₃ are independently selectedfrom the group consisting of hydrido and halo; R₅, R₆, R₇, R₁₀, R₁₁, andR₁₂ are independently selected from the group consisting of hydrido,alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino,arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy,aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl,cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy,heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, andheteroarylsulfonyl.
 7. The compound as recited in claim 6 or apharmaceutically acceptable salt thereof wherein; n is the integer 1;R₁₆ is hydrido; R₁ is selected from the group consisting oftrifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido, methyl, ethyl,propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,and 2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂; Y is acovalent single bond; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃are independently selected from the group consisting of hydrido andfluoro; R₅ and R₁₀ are independently selected from the group consistingof 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy,4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy,4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy,chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl,3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy,4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy,3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy,3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy,4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl,4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy,tert-butoxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio; R₆ and R₁₁ areindependently selected from the group consisting of chloro, fluoro,hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl,and trifluoromethoxy; R₇ and R₁₂ are independently selected from thegroup consisting of hydrido, fluoro, and trifluoromethyl.
 8. Thecompound as recited in claim 7 or a pharmaceutically acceptable saltthereof, wherein; n is the integer 1; R₁₆ is hydrido; R₁ is selectedfrom the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido, methyl, ethyl,phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl,1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, and2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR )_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, andchlorodifluoromethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has alower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and ahigher Cahn-Ingold-Prelog stereochemical system ranking than R₂; Y is acovalent single bond; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃are independently selected from the group consisting of hydrido andfluoro; R₅ and R₁₀ are independently selected from the group consistingof benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy,2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy,3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy,3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino,5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy,cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy,difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy,4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl,4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy,3-fluorophenoxy, 3-fluoro-2-nitrophenoxy,2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl,3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl,2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy,3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy,thiophen-3-yl,tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy,1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy,2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl,3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of chloro, fluoro, hydrido, pentafluoroethyl,1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇and R₁₂ areindependently selected from the group consisting of hydrido, fluoro, andtrifluoromethyl.
 9. The compound as recited in claim 6 or apharmaceutically acceptable salt thereof wherein; n is the integer 1;R₁₆ is hydrido; R₁ is selected from the group consisting oftrifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido, methyl, ethyl,propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,and 2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂; Y is oxy; Z isa covalent single bond; R₄, R₈, R₉, and R₁₃ are independently selectedfrom the group consisting of hydrido and fluoro; R₅ and R₁₀ areindependently selected from the group consisting of 4-aminophenoxy,benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy,4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy,4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy,chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl,3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy,4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy,3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy,3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy,4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl,4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy,tert-butoxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio; R₆ and R₁₁ areindependently selected from the group consisting of chloro, fluoro,hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl,and trifluoromethoxy; R₇ and R₁₂ are independently selected from thegroup consisting of hydrido, fluoro, and trifluoromethyl.
 10. Thecompound as recited in claim 9 or a pharmaceutically acceptable saltthereof, wherein; n is the integer 1; R₁₆ is hydrido; R₁ is selectedfrom the group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido, methyl, ethyl,phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl,1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, and2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, andchlorodifluoromethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has alower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and ahigher Cahn-Ingold-Prelog stereochemical system ranking than R₂; Y isoxy; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃ are independentlyselected from the group consisting of hydrido and fluoro; R₅ and R₁₀ areindependently selected from the group consisting of benzyloxy,5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy,4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy,4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy,3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy,3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino,5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy,cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy,difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy,4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl,4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy,3-fluorophenoxy, 3-fluoro-2-nitrophenoxy,2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl,3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl,2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy,3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy,thiophen-3-yl,tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy,1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy,2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl,3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of chloro, fluoro, hydrido, pentafluoroethyl,1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ areindependently selected from the group consisting of hydrido, fluoro, andtrifluoromethyl.
 11. The compound as recited in claim 6 or apharmaceutically acceptable salt thereof, wherein; n is the integer 1;R₁₆ is hydrido; R₁ is selected from the group consisting oftrifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(HII-P);

R₂ is selected from the group consisting of hydrido, methyl, ethyl,propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,and 2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂; Y is selectedfrom the group consisting of methylene and ethylene; Z is a covalentsingle bond; R₄, R₈, R₉, and R₁₃ are independently selected from thegroup consisting of hydrido and fluoro; R₅ and R₁₀ are independentlyselected from the group consisting of 4-aminophenoxy, benzoyl, benzyl,benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy,4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro,3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl,3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy,4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy,3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy,3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy,4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl,4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenyl amino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy,tert-butoxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-l1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio; R₆ and R₁₁ areindependently selected from the group consisting of chloro, fluoro,hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl,and trifluoromethoxy; R₇and R₁₂ are independently selected from thegroup consisting of hydrido, fluoro, and trifluoromethyl.
 12. Thecompound as recited in claim 11 or a pharmaceutically acceptable saltthereof, wherein; n is the integer 1; R₆ is hydrido; R₁ is selected fromthe group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido, methyl, ethyl,phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl,1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, and2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, andchlorodifluoromethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has alower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and ahigher Cahn-Ingold-Prelog stereochemical system ranking than R₂; Y ismethylene; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and fluoro;R₅ and R₁₀ are independently selected from the group consisting ofbenzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy,2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy,3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy,3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino,5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy,cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy,difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy,4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl,4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy,3-fluorophenoxy, 3-fluoro-2-nitrophenoxy,2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl,3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl,2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy,3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy,thiophen-3-yl,tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy,1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy,2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl,3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of chloro, fluoro, hydrido, pentafluoroethyl,1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ areindependently selected from the group consisting of hydrido, fluoro, andtrifluoromethyl.
 13. The compound as recited in claim 6 or apharmaceutically acceptable salt, wherein; n is the integer 1; R₁₆ ishydrido; R₁ is haloalkyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido, alkyl, haloalkyl,aryl, and haloalkoxy with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, alkyl, andhaloalkyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂; Y is acovalent single bond; Z is covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and halo;R₅, R₆, R₇, R₁₁, and R₁₂ are independently selected from the groupconsisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl,heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
 14. Thecompound as recited in claim 13 or a pharmaceutically acceptable saltthereof, wherein; n is the integer 1; R₁ is selected from the groupconsisting of trifluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₁₆ is hydrido; R₂ is selected from the group consisting of hydrido andphenyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog systemranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp; R₃ is selected from thegroup consisting of hydrido, methyl, trifluoromethyl, and difluoromethylwith the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂; Y is a covalent single bond; Z isa covalent single bond; R₄, R₈, R₉, and R₁₃ are independently selectedfrom the group consisting of hydrido and fluoro; R₅ is selected from thegroup consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy,2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy,3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy,3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy,3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy,3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consistingof cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl,1,1-bis-trifluoromethyl-1-hydroxymethyl, isobutyl, isopropoxy,pentafluoroethyl, trifluoromethoxy, trifluoromethyl, andtrifluoromethylthio; R₆and R₁₁ are independently selected from the groupconsisting of fluoro and hydrido; R₇ and R₁₂ are independently selectedfrom the group consisting of hydrido and fluoro.
 15. The compound asrecited in claim 14 or a pharmaceutically acceptable salt thereof,wherein; n is the integer 1; R₁ is selected from the group consisting oftrifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₁₆ ishydrido; R₂ is hydrido; R₃is hydrido; Y is a covalent single bond; Z isa covalent single bond; R₄, R₈, R₉, and R₁₃ are independently selectedfrom the group consisting of hydrido and fluoro; R₅ is selected from thegroup consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy,2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy,3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy,3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy,3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy,3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consistingof 1,1,2,2-tetrafluoroethoxy, pentafluoroethyl, and trifluoromethyl; R₆and R₁₁ are independently selected from the group consisting of fluoroand hydrido; R₇ and R₁₂ are independently selected from the groupconsisting of hydrido and fluoro.
 16. The compound as recited in claim 6or a pharmaceutically acceptable salt, wherein; n is the integer 1; R₁ ₆is hydrido; R₁ is haloalkyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₂ is selected from the group consisting of hydrido, alkyl, haloalkyl,aryl, and haloalkoxy with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, alkyl, andhaloalkyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂; Y is oxy; Z isa covalent single bond; R₄, R₈, R₉, and R₁₃ are independently selectedfrom the group consisting of hydrido and halo; R₅, R₆, R₇, R₁₀, R₁₁, andR₁₂ are independently selected from the group consisting of hydrido,alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino,arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy,aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl,cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy,heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, andheteroarylsulfonyl.
 17. The compound as recited in claim 16 or apharmaceutically acceptable salt thereof, wherein; n is the integer 1;R₁ is selected from the group consisting of trifluoromethyl,chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ hasa higher Cahn-Ingold-Prelog stereochemical system ranking than both R2and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₁₆ is hydrido; R₂ is selected from the group consisting of hydrido andphenyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog systemranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp; R₃ is selected from thegroup consisting of hydrido, methyl, trifluoromethyl, and difluoromethylwith the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂; Y is oxy; Z is a covalent singlebond; R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido and fluoro; R₅ is selected from the groupconsisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy,2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy,3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy,3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy,3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy,3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consistingof cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl,1,1-bis-trifluoromethyl-1-hydroxymethyl, isobutyl, isopropoxy,pentafluoroethyl, trifluoromethoxy, trifluoromethyl, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of fluoro and hydrido; R₇ and R₁₂ are independentlyselected from the group consisting of hydrido and fluoro.
 18. Thecompound as recited in claim 17 or a pharmaceutically acceptable saltthereof, wherein; n is the integer 1; R₁ is selected from the groupconsisting of trifluoromethyl, chlorodifluoromethyl, andpentafluoroethyl; R₁₆ is hydrido; R₂ is hydrido; R₃ is hydrido; Y isoxy; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃ are independentlyselected from the group consisting of hydrido and fluoro; R₅ is selectedfrom the group consisting of 5-bromo-2-fluorophenoxy,4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy,3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy,4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy,3-pentafluoroethylphenoxy, 3-tert-butylphenoxy,3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy,3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ isselected from the group consisting of 1,1,2,2-tetrafluoroethoxy,pentafluoroethyl, and trifluoromethyl; R₆ and R₁₁ are independentlyselected from the group consisting of fluoro and hydrido; p1 R₇ and R₁₂are independently selected from the group consisting of hydrido andfluoro.
 19. The compound as recited in claim 6 or a pharmaceuticallyacceptable salt, wherein; n is the integer 1; R₁₆ is hydrido; R₁ ishaloalkyl with the proviso that R₁ has a higher Cahn-Ingold-Prelogstereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qpwherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₂ is selected from the group consisting of hydrido, alkyl, haloalkyl,aryl, and haloalkoxy with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;R₃ is selected from the group consisting of hydrido, alkyl, andhaloalkyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂; Y ismethylene; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and halo;R₅, R₆, R₇, R₁₀, R₁₁, and R₂ are independently selected from the groupconsisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl,heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
 20. Thecompound as recited in claim 19 or a pharmaceutically acceptable saltthereof, wherein; n is the integer 1; R₁ is selected from the groupconsisting of trifluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula(III-P);

R₁₆ is hydrido; R₂ is selected from the group consisting of hydrido andphenyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog systemranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp; R₃ is selected from thegroup consisting of hydrido, methyl, trifluoromethyl, and difluoromethylwith the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂; Y is methylene; Z is a covalentsingle bond; R₄, R₈, R₉, and R₁₃ are independently selected from thegroup consisting of hydrido and fluoro; R₅ is selected from the groupconsisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy,2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy,3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy,3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy,3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy,3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consistingof cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl,1,1-bis-trifluoromethyl-1-hydroxymethyl, isobutyl, isopropoxy,pentafluoroethyl, trifluoromethoxy, trifluoromethyl, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of fluoro and hydrido; R₇ and R₁₂ are independentlyselected from the group consisting of hydrido and fluoro.
 21. A compoundas recited in claim 2 having the formula:

or a pharmaceutically acceptable salt thereof, wherein; D₁, D₂, J₁, J₂and K₁ are each carbon with the proviso that at least one of D₃, D₄, J₃,J₄ and K₂ is selected from the group consisting of O, S, and N, whereinD₃, D₄, J₃, J₄ and K₂ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that nomore than one of D₃, D₄, J₃, J₄ and K₂ is a covalent bond, no more thanone of D₃, D₄, J₃, J₄ and K₂ is O, no more than one of D₃, D₄, J₃, J₄and K₂ is S, one D₃, D₄, J₃, J₄ and K₂ must be a covalent bond when twoof D₃, D₄, J₃, J₄ and K₂ are O and S, and no more than four of D₃, D₄,J₃, J₄ and K₂ are N; D₁, D₂, J₁, J₂ and K₁ are independently selectedfrom the group consisting of C, O, S, N and covalent bond with theprovisos that D₃, D₄, J₃, J₄ and K₂ are each carbon and at least one ofD₁, D₂, J₁, J₂ and K₁ is selected from the group consisting of O, S, andN wherein, when D₁, D₂, J₁, J₂ and K₁ are selected from the groupconsisting of C, O, S, covalent bond, and N, no more than one of D₁, D₂,J₁, J₂ and K₁ is a covalent bond, no more than one of D₁, D₂, J₁J₂ andK₁ is O, no more than one of D₁, D₂, J₁, J₂ and K₁ is S, one of D₁, D₂,J₁, J₂ and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁are O and S, and no more than four of D₁, D₂, J₁, J₂ and K₁ are N; n isan integer selected from 1 and 2; X is oxy; R₁₆ is selected from thegroup consisting of hydrido and a spacer selected from the groupconsisting of a covalent single bond and a linear spacer moiety having achain length of 1 to 4 atoms linked to the point of bonding of anyaromatic substituent selected from the group consisting of R₄, R₈, R₉,and R₁₃ to form a heterocyclyl ring having from 5 through 10 contiguousmembers; R₁ is selected from the group consisting of haloalkyl andhaloalkoxymethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₂ is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(Ap)Qp; R₃ is selected from the group consisting of hydrido,aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl with the provisosthat (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemicalsystem ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than R₂; Y is selected from the group consisting of acovalent single bond, (CH₂)_(q) wherein q is an integer selected from 1and 2, and (CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integersindependently selected from 0 and 1; Z is selected from the groupconsisting of covalent single bond, (CH₂)_(q) wherein q is an integerselected from 1 and 2, and (CH₂)_(j)—O—(CH₂)_(k) wherein j and k areintegers independently selected from 0 and 1; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido, halo,haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino,heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl,heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl; R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ are independentlyselected to form spacer pairs wherein a spacer pair is taken together toform a linear moiety having from 3 through 6 contiguous atoms connectingthe points of bonding of said spacer pair members to form a ringselected from the group consisting of a cycloalkenyl ring having 5through 8 contiguous members, a partially saturated heterocyclyl ringhaving 5 through 8 contiguous members, a heteroaryl ring having 5through 6 contiguous members, and an aryl with the provisos that no morethan one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆,R₆ and R₇, and R₇ and R₈, is used at the same time and that no more thanone of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ is used at the same time.
 22. The compound asrecited in claim 21 or a pharmaceutically acceptable salt thereof,wherein; D₁, D₂, J₁, J₂ and K₁ are each carbon with the proviso that atleast one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consistingof O, S, and N, wherein D₃, D₄, J₃, J₄ and K₂ are independently selectedfrom the group consisting of C, N, O, S and covalent bond with theprovisos that no more than one of D₃, D₄, J₃, J₄ and K₂ is a covalentbond, no more than one of D₃, D₄, J₃, J₄ and K₂ is O, no more than oneof D₃, D₄, J₃, J₄ and K₂ is S, one of D₃, D₄, J₃, J₄ and K₂ must be acovalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no morethan four of D₃, D₄, J₃, J₄ and K₂ are N; D₁, D₂, J₁, J₂ and K₁ areindependently selected from the group consisting of C, O, S, N andcovalent bond with the provisos that D₃, D₄, J₃, J₄ and K₂ are eachcarbon and at least one of D₁, D₂, J₁, J₂ and K₁ is selected from thegroup consisting of O, S, and N wherein, when D₁, D₂, J₁, J₂ and K₁ areselected from the group consisting of C, O, S, covalent bond, and N, nomore than one of D₁, D₂, J₁, J₂ and K₁ is a covalent bond, no more thanone of D₁, D₂, J₁, J₂ and K₁ is O, no more than one of D₁, D₂, J₁, J₂and K₁ is S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond whentwo of D₁, D₂, J₁, J₂ and K₁ are O and S. and no more than four of D₁,D₂, J₁, J₂ and K₁ are N; n is the integer 1; X is oxy; R₁₆ is takentogether with R₄, R₈, R₉, or R₁₃ to form a spacer selected from thegroup consisting of a covalent single bond, CH₂, CH(CH₃), CF₂, C(O),C(S), and SO₂; R₁ is selected from the group consisting oftrifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₂ is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, vinyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, and 2,2,3,3,3-pentafluoropropylwith the proviso that R₂ has a lower Cahn-Ingold-Prelog system rankingthan both R₁ and (CHR₃)_(n)—N(A)Q; R₃ is selected from the groupconsisting of hydrido, methyl, ethyl, vinyl, phenyl,4-trifluoromethylphenyl, , trifluoromethyl, trifluoromethoxymethyl,difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with theprovisos that (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂; Y is selected from the groupconsisting of covalent single bond, oxy, methyleneoxy, methylene, andethylene; Z is selected from the group consisting of covalent singlebond, oxy, methyleneoxy, methylene, and ethylene; R₄, R₈, R₉, and R₁₃are independently selected from the group consisting of hydrido andfluoro; R₅ and R₁₀ are independently selected from the group consistingof 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy,4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy,4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy,chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl,3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy,4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy,3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy,3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy,4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl,4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy,tert-butoxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio; R₆ and R₁₁ areindependently selected from the group consisting of chloro, fluoro,hydrido, difluoromethoxy, trifluoromethyl, trifluoromethoxy,pentafluoroethyl, and 1,1,2,2-tetrafluoroethoxy; R₇ and R₁₂ areindependently selected from the group consisting of hydrido, fluoro, andtrifluoromethyl.
 23. The compound as recited in claim 21 or apharmaceutically acceptable salt thereof, wherein: D₁, D₂, J₁, J₂ and K₁are each carbon with the proviso that at least one of D₃, D₄, J₃, J₄ andK₂ is selected from the group consisting of O, S, and N, wherein D₃, D₄,J₃, J₄ and K₂ are independently selected from the group consisting of C,N, O, S and covalent bond with the provisos that no more than one of D₃,D₄, J₃, J₄ and K₂ is a covalent bond, no more than one of D₃, D₄, J₃, J₄and K₂ is O, no more than one of D₃, D₄, J₃, J₄ and K₂ is S, one of D₃,D₄, J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ andK₂ are O and S, and no more than four of D₃, D₄, J₃, J₄and K₂ are N; D₁,D₂, J₁, J₂ and K₁ are selected from the group consisting of C, O, S, Nand covalent bond with the provisos that D₃, D₄, J₃, J₄ and K₂ are eachcarbon and at least one of D₁, D₂, J₁, J₂ and K₁ is selected from thegroup consisting of O, S, and N wherein, when D₁, D₂, J₁, J₂ and K₁ areselected from the group consisting of C, O, S, covalent bond, and N, nomore than one of D₁, D₂, J₁, J₂ and K₁ is a covalent bond, no more thanone of D₁, D₂, J₁, J₂ and K₁ is O, no more than one of D₁, D₂, J₁, J₂and K₁ is S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond whentwo of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁,D₂, J₁, J₂ and K₁ are N; n is an integer selected from 1 and 2; X isoxy; R₁ is selected from the group consisting of haloalkyl andhaloalkoxymethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₁₆ is hydrido; R₂ is selected from the group consisting of hydrido,aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl with the provisothat R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and(CHR₃)_(n)—N(A)Q; R₁ is selected from the group consisting of hydrido,aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl with the provisosthat (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelog stereochemicalsystem ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemicalsystem ranking than R₂; Y is selected from the group consisting of acovalent single bond, oxy and C1-C2 alkylene; Z is a covalent singlebond; R₄, R₈, R₉, and R₁₃ are independently selected from the groupconsisting of hydrido and halo; R₄, R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ areindependently selected from the group consisting of hydrido, alkyl,halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio,aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl,cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl,cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy,heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, andheteroarylsulfonyl.
 24. The compound as recited in claim 23 andpharmaceutically acceptable salts, wherein; n is the integer 1; X isoxy; R₁₆ is hydrido; R₁ is selected from the group consisting oftrifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₂ is selected from the group consisting of hydrido, methyl, ethyl,propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,and 2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q; R₃is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the provisos that (CHR₃)_(n)—N(A)Q has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂; Y is selectedfrom the group consisting of a single covalent bond, methylene,ethylene, and oxy; Z is covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and fluoro;R₅ and R₁₀ are independently selected from the group consisting of4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy,4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy,4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy,chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl,3-chloro4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy,4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy,3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy,3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy,4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl,4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy,tert-butoxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio; R₆ and R₁₁ areindependently selected from the group consisting of chloro, fluoro,hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl,and trifluoromethoxy; R₇ and R₁₂ are independently selected from thegroup consisting of hydrido, fluoro, and trifluoromethyl.
 25. Thecompound as recited in claim 24 or a pharmaceutically acceptable saltthereof, wherein; n is the integer 1; X is oxy; R₁ is selected from thegroup consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl,trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₁₆ is hydrido; R₂ is selected from the group consisting of hydrido,methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl,1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, and2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q; R₃is selected from the group consisting of hydrido, phenyl,4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, andchlorodifluoromethyl with the provisos that (CHR₃)_(n)—N(A)Q has a lowerCahn-Ingold-Prelog stereochemical system ranking than R₁ and a higherCahn-Ingold-Prelog stereochemical system ranking than R₂; Y ismethylene; Z is covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and fluoro;R₅ and R₁ are independently selected from the group consisting ofbenzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy,2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy,3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy,3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino,5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy,cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy,difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy,4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl,4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy,3-fluorophenoxy, 3-fluoro-2-nitrophenoxy,2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl,3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl,2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy,3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy,thiophen-3-yl,tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy,1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy,2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl,3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of chloro, fluoro, hydrido, pentafluoroethyl,1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ areindependently selected from the group consisting of hydrido, fluoro, andtrifluoromethyl.
 26. The compound as recited in claim 23 or apharmaceutically acceptable salt, wherein; D₁, D₂, J₁, J₂ and K₁ areeach carbon; D₃, D₄, J₃, J₄ and K₂ are independently selected from thegroup consisting of C, N, O, S and covalent bond with the provisos thatno more than one of D₃, D₄, J₃, J₄ and K₂ is a covalent bond, no morethan one of D₃, D₄, J₃, J₄ and K₂ is O, no more than one of D₃, D₄, J₃,J₄ and K₂ is S, one of D₃, D₄, J₃, J₄ and K₂ must be a covalent bondwhen two of D₃, D₄, J₃, J₄ and K₂ are O and S, no more than four of D₃,D₄, J₃, J₄ and K₂ are N, and one of D₃, D₄, J₃, J₄ and K₂ is selectedfrom the group consisting of O, S, and N; n is the integer 1; X is oxy;R₁₆ is hydrido; R₁ is haloalkyl with the proviso that R₁ has a higherCahn-Ingold-Prelog stereochemical system ranking than both R₂ and(CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₂ is selected from the group consisting of hydrido, alkyl, aryl,haloalkyl, and haloalkoxy with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q; R₃is selected from the group consisting of hydrido, alkyl, and haloalkylwith the provisos that (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂; Y is a C1-C2 alkylene; Z iscovalent single bond; R₁₄ is hydrido; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and halo;R₅, R₆, R₇, R₁₀, R₁₁ and R₁₂ are independently selected from the groupconsisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, and heteroaryloxyalkyl.
 27. Thecompound as recited in claim 23 or a pharmaceutically acceptable salt,wherein; D₃, D₄, J₃, J₄ and K₂ are each carbon; D₁, D₂, J₁, J₂ and K₁are independently selected from the group :consisting of C, N, O, S andcovalent bond with the provisos that no more than one of D₁, D₂, J₁, J₂and K₁ is a covalent bond, no more than one of D₁, D₂, J₁, J₂and K₁is O,no more than one of D₁, D₂, J₁, J₂and K₁ is S, one of D₁, D₂, J₁, J₂ andK₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O andS, no more than four of D₁, D₂, J₁, J₂ and K₁ are N, and one of D₁, D₂,J₁, J₂ and K₁ is selected from the group consisting of O, S, and N; n isthe integer 1; X is oxy; R₁₆ is hydrido; R₁ is haloalkyl with theproviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical systemranking than both R₂ and (CHR₃)_(n)—N(A)Q wherein A is Formula (II) andQ is Formula (III);

R₂ is selected from the group consisting of hydrido, alkyl, aryl,haloalkyl, and haloalkoxy with the proviso that R₂ has a lowerCahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q; R₃is selected from the group consisting of hydrido, alkyl, and haloalkylwith the provisos that (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelogstereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelogstereochemical system ranking than R₂; Y is a C1-C2 alkylene; Z iscovalent single bond; R₁₄ is hydrido; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and halo;R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, and heteroaryloxyalkyl.
 28. Thecompound as recited in any one of claims 26 or 27 or a pharmaceuticallyacceptable salt thereof, wherein; n is the integer 1; X is oxy; R₁ isselected from the group consisting of trifluoromethyl andpentafluoroethyl and chlorodifluoromethyl; R₁₆ is hydrido; R₂ ishydrido; R₃ is selected from the group consisting of hydrido, methyl,trifluoromethyl, and difluoromethyl; Y is methylene; Z is a covalentsingle bond; R₄, R₈, R₉, and R₁₃ are independently selected from thegroup consisting of hydrido and fluoro; R₅ is selected from the groupconsisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy,2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy,3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy,3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy,3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy,3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consistingof cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl,1,1-bis-trifluoromethyl-1-hydroxymethyl, isobutyl, isopropoxy,pentafluoroethyl, trifluoromethoxy, trifluoromethyl, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of fluoro and hydrido; R₇ and R₁₂ are independentlyselected from the group consisting of hydrido and fluoro.
 29. A compoundhaving the formula:

or a pharmaceutically acceptable salt thereof, wherein: n is an integerselected from 1 and 2; R₁ is selected from the group consisting ofhaloalkyl and haloalkoxyalkyl; R₁₆ is hydrido; R₂ is hydrido; R₃ ishydrido; Y is selected from the group consisting of a covalent singlebond and C1-C2 alkylene; Z is selected from the group consisting of acovalent single bond and C1-C2 alkylene; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and halo;R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy,heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl,heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
 30. Thecompound as recited in claim 29 or a pharmaceutically acceptable saltthereof wherein; n is the integer 1; R₁₆ is hydrido; R₁ is selected fromthe group consisting of trifluoromethyl,1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl,chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃ ishydrido; Y is selected from the group consisting of methylene, andethylene; Z is selected from the group consisting of covalent singlebond and methylene; R₄, R₈, R₉, and R₁₃ are independently selected fromthe group consisting of hydrido and fluoro; R₅ and R₁₀ are independentlyselected from the group consisting of 4-aminophenoxy, benzoyl, benzyl,benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy,4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro,3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy,4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl,3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy,4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy,3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy,2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl,cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl,cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy,3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy,3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy,3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl,1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy,4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy,3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl,4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy,2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy,3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy,4-fluoro-2-trifluoromethylbenzyloxy,4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy,4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl,1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy,3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy,3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio,4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy,3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy,propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl,4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy,4-tert-butylphenoxy, 1,1,2 ,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy,2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl,3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,2,4-bis-trifluoromethylbenzyloxy,1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl,3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,3-trifluoromethylphenoxy, 3-trifluoromethylphenyl,3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy,2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, and trifluoromethylthio; R₆ and R₁₁ areindependently selected from the group consisting of chloro, fluoro,hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl,and trifluoromethoxy; R₇ and R₁₂ are independently selected from thegroup consisting of hydrido, fluoro, and trifluoromethyl.
 31. Thecompound as recited in claim 30 or a pharmaceutically acceptable saltthereof, wherein; n is the integer 1; R₁ is selected from the groupconsisting of trifluoromethyl, difluoromethyl, chlorodifluoromethyl, andpentafluoroethyl; R₁₆ is hydrido; R₂ is hydrido; R₃ is hydrido; Y ismethylene; Z is covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and fluoro;R₅ and R₁₀ are independently selected from the group consisting ofbenzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy,2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy,3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy,3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino,5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy,cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy,2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl,3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy,3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy,difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl,2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy,3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy,4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl,4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy,3-fluorophenoxy, 3-fluoro-2-nitrophenoxy,2-fluoro-3-trifluoromethylbenzyloxy,3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy,2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy,4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl,3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl,2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy,3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl,4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy,3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy,1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy,2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl,pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl,1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy,phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy,thiophen-3-yl,tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy,1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl,2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy,2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy,3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy,4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl,3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl,3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy,4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy,3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy,3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy,3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy,3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, andtrifluoromethylthio; R₆ and R₁₁ are independently selected from thegroup consisting of chloro, fluoro, hydrido, pentafluoroethyl,1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ areindependently selected from the group consisting of hydrido, fluoro, andtrifluoromethyl.
 32. The compound as recited in claim 29 or apharmaceutically acceptable salt, wherein; n is the integer 1; R₁₆ ishydrido; R₁ is haloalkyl; R₂ is is hydrido; R₃ is is hydrido; Y ismethylene; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and halo;R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the groupconsisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl,cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl,halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio,aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl,cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl,cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, andheteroaryloxyalkyl.
 33. The compound as recited in claim 32 or apharmaceutically acceptable salt, wherein; n is the integer 1; R₁₆ ishydrido; R₁ is haloalkyl; R₂ is is hydrido; R₃ is is hydrido; Y ismethylene; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and halo; R₅is selected from the group consisting of perhaloaryloxy,N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio,hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, haloalkyl, haloalkoxy, aryl,alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy,heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy,cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio,hydroxyhaloalkyl, heteroaralkoxy, and heteroaryloxyalkyl. R₁₀ isselected from the group consisting of haloalkyl, haloalkoxy, aryl,alkylthio, alkoxy, aralkyl, alkyl, cycloalkoxy, cycloalkylalkoxy,heteroaryl, cycloalkyl, haloalkylthio, and hydroxyhaloalkyl. R₆ and R₁₁are independently selected from the group consisting of hydrido andhalo; R₇ and R₁₂ are independently selected from the group consisting ofhydrido and halo.
 34. The compound as recited in claim 33 or apharmaceutically acceptable salt thereof, wherein; n is the integer 1;R₁ is trifluoromethyl; R₁₆ is hydrido; R₂ is hydrido; R₃ is hydrido; Yis methylene; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and fluoro;R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy,4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy,3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy,4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy,3-pentafluoroethylphenoxy, 3-tert-butylphenoxy,3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy,3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ isselected from the group consisting of cyclopentyl,1,1,2,2-tetrafluoroethoxy, 2-furyl,1,1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethyl, and trifluoromethylthio; R₆ and R₁₁are independently selected from the group consisting of fluoro andhydrido; R₇ and R₁₂ are independently selected from the group consistingof hydrido and fluoro.
 35. The compound as recited in claim 34 or apharmaceutically acceptable salt thereof, wherein; n is the integer 1;R₁ is trifluoromethyl; R₁₆ is hydrido; R₂ is hydrido; R₃ is hydrido; Yis methylene; Z is a covalent single bond; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido and fluoro;R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy,4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy,3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy,3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy,4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy,3-pentafluoroethylphenoxy, 3-tert-butylphenoxy,3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy,3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ isselected from the group consisting of 1,1,2,2-tetrafluoroethoxy,pentafluoroethyl, and trifluoromethyl; R₆ and R₁₁ are independentlyselected from the group consisting of fluoro and hydrido; R₇ and R₁₂ areindependently selected from the group consisting of hydrido and fluoro.36. A compound as recited in claim 29 or a pharmaceutically acceptablesalt thereof wherein said compound is selected from the group consistingof:(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-(2-fury)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoro-methyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.37. A pharmaceutical composition comprising a compound of one of claims1 through 36 together with a pharmaceutically acceptable carrier.
 38. Amethod of treating coronary artery disease or other CETP-mediateddisorders in a subject by administering a therapeutically effectiveamount of a compound of one of claims 1 through
 36. 39. A method ofpreventing coronary artery disease or other CETP-mediated disorders in asubject by administering a therapeutically effective amount of acompound of one of claims 1 through
 36. 40. A method of preventingcerebral vascular accident (CVA) in a subject by administering atherapeutically effective amount of a compound of one of claims 1through
 36. 41. A method of preventing or treating dyslipidemia in asubject by administering a therapeutically effective amount of acompound of one of claims 1 through
 36. 42. A process for thepreparation of compounds as recited in any one of claims 1 or 2 havingthe Formula (IV):

and pharmaceutically acceptable salts thereof, comprising the reactionof an amine of Formula (V):

with an epoxide of Formula (XX-R):

wherein; R₁ is selected from the group consisting of haloalkyl andhaloalkoxymethyl; R₂ is selected from the group consisting of hydrido,aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl; R₃ isselected from the group consisting of hydrido, aryl, alkyl, alkenyl,haloalkyl, and haloalkoxyalkyl; D and E are independently selected fromthe group consisting hydrido, A, and Q with the provisos that E and Dare other than hydrido at the same time and A and Q are independentlyselected, when one of E and D is hydrido or when Y and Z are both singlecovalent bonds, from other than phenyl, 3-methylphenyl, 3-ethylphenyl,2-methoxy-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, and3-bromophenyl; A is the Formula:

Q is the Formula:

D₁, D₂, J₁, J₂ and K₁ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that nomore than one of D₁, D₂, J₁, J₂ and K₁ is a covalent bond, no more thanone of D₁, D₂, J₁, J₂ and K₁ is O, no more than one of D₁, D₂, J₁, J₂and K₁ is S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond whentwo of D₁, D₂, J₁, J₂and K₁ are O and S, and no more than four of D₁,D₂, J₁, J₂ and K₁ are N; D₃, D₄, J₃, J₄ and K₂ are independentlyselected from the group consisting of C, N, O, S and covalent bond withthe provisos that no more than one is a covalent bond, no more than oneof D₃, D₄, J₃, J₄ and K₂ is O, no more than one of D₃, D₄, J₃, J₄ and K₂is S, no more than two of D₃, D₄, J₃, J₄ and K₂ are O and S, one of D₃,D₄, J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ andK₂ are O and S, and no more than four of D₃, D₄, J₃, J₄ and K₂ are N; Yis selected from the group consisting of a covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 and 2, and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 and 1; Z is selected from the group consisting ofcovalent single bond, (CH₂)_(q) wherein q is an integer selected from 1and 2, and (CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integersindependently selected from 0 and 1; R₄, R₈, R₉, and R₁₃ areindependently selected from the group consisting of hydrido, halo,haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁ and R₁₂ are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino,heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl,heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl,carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl; R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈,R₉, and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ are independentlyselected to form spacer pairs wherein a spacer pair is taken together toform a linear moiety having from 3 through 6 contiguous atoms connectingthe points of bonding of said spacer pair members to form a ringselected from the group consisting of a cycloalkenyl ring having 5through 8 contiguous members, a partially saturated heterocyclyl ringhaving 5 through 8 contiguous members, a heteroaryl ring having 5through 6 contiguous members, and an aryl with the provisos that no morethan one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆,R₆ and R₇, and R₇ and R₈, is used at the same time and that no more thanone of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁and R₁₂, and R₁₂ and R₁₃ is used at the same time.
 43. A processaccording to claim 42 wherein the reaction is carried out at atemperature of from 0° C. to 100° C.
 44. A process according to claim 43wherein the reaction is carried out at a temperature of from 15° C. to65° C.
 45. A process according to claim 42 wherein the process furthercomprises a solvent selected from the group consisting oftetrahydrofuran, dioxane, methylene chloride, and acetonitrile.
 46. Aprocess according to claim 42 wherein the process further comprises atransition metal salt catalyst selected from the group consisting ofytterbium, hafnium, scandium, neodynium, gadolium, and zirconium salts.47. A process according to claim 46 wherein the transition metal salt isselected from the group consisting of ytterbium triflate, hafniumtriflate, scandium triflate, neodynium triflate, gadolium triflate, andzirconium triflate.
 48. A process according to claim 42 wherein theoxirane XX-R is selected from the group consisting of2-trifluoromethyloxirane, 2-pentafluoroethyloxirane,2-(1,1,2,2-tetrafluoroethoxymethyl)oxirane,2-(difluorochloromethyl)oxirane, and 2-(trifluoromethoxymethyl)oxirane.49. A process according to claim 42 in which the oxirane has the(R)-chiral configuration at the R₁ and R₂ substituted carbon.
 50. Aprocess according to claim 42, wherein; D₁, D₂, J₁, J₂ and K₁ are eachcarbon; D₃, D₄, J₃, J₄ and K₂ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that atleast one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consistingof O, S, and N, wherein no more than one of D₃, D₄, J₃, J₄ and K₂ is acovalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ is O, no morethan one of D₃, D₄, J₃, J₄ and K₂ is S, one of D₃, D₄, J₃, J₄ and K₂must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S,and no more than four of D₃, D₄, J₃, J₄ and K₂ are N.
 51. A processaccording to claim 42 wherein; D₃, D₄, J₃, J₄ and K₂ are each carbon;D₁, D₂, J₁, J₂ and K₁ are independently selected from the groupconsisting of C, N, O, S and covalent bond with the provisos that atleast one of D₁, D₂, J₁, J₂ and K₁ is selected from the group consistingof O, S, and N, wherein no more than one of D₁, D₂, J₁, J₂ and K₁ is acovalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ is O, no morethan one of D₁, D₂, J₁, J₂ and K₁ is S, one of D₁, D₂, J₁, J₂ and K₁must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O and S,and no more than four of D₁, D₂, J₁, J₂ and K₁ are N.
 52. A processaccording to claim 42 wherein D₁, D₂, J₁, J₂, K₁, D₃, D₄, J₃, J₄ and K₂are each carbon.
 53. A process according to claim 42 wherein; D₁, D₂,J₁, J₂, K₁, D₃, D₄, J₃, J₄ and K₂ are each carbon Y is selected from thegroup consisting of a covalent single bond and (CH₂)_(q) wherein q is aninteger selected from 1 and 2, and (CH₂)_(j)—O—(CH₂)_(k) wherein j and kare integers independently selected from 0 and 1; Z is a covalent singlebond;
 54. A process according to claim 42 wherein; D₁, D₂, J₁, J₂, K₁,D₃, D₄, J₃, J₄ and K₂ are each carbon Y is selected from the groupconsisting of a covalent single bond and C1-C2 alkylene; Z is a covalentsingle bond; R₄, R₈, R₉, and R₁₃ are independently selected from thegroup consisting of hydrido and halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ areindependently selected from the group consisting of hydrido, alkyl,halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio,aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl,cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl,cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy,heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, andheteroarylsulfonyl.
 55. A process according to any of claims 50 through54 wherein the reaction is carried out at a temperature of from 0° C. to100° C.
 56. A process according to claim 55 wherein the reaction iscarried out at a temperature of from 15° C. to 65° C.
 57. A processaccording to any of claims 50 through 54 wherein the process furthercomprises a solvent selected from the group consisting oftetrahydrofuran, dioxane, methylene chloride, and acetonitrile.
 58. Aprocess according to any of claims 50 through 54 wherein the processfurther comprises a transition metal salt catalyst selected from thegroup consisting of ytterbium, hafnium, scandium, neodynium, gadolium,and zirconium salts.
 59. A process according to claim 58 in which thetransition metal salt is selected from the group consisting of ytterbiumtriflate, hafnium triflate, scandium triflate, neodynium triflate,gadolium triflate, and zirconium triflate.
 60. A process according toany of claims 50 through 54 wherein the oxirane XX-R is selected fromthe group consisting of 2-trifluoromethyloxirane,2-pentafluoroethyloxirane, 2-(1,1,2,2-tetrafluoroethoxymethyl)oxirane,2-(difluorochloromethyl)oxirane, and 2-(trifluoromethoxymethyl)oxirane.61. A process according to claim 60 in which the oxirane has the(R)-chiral configuration at the R₁ and R₂ substituted carbon.
 62. Aprocess according to any of claims 50 through 54 wherein the processfurther comprises a: (a) Temperature of from 0° C. to 100° C.; (b)Non-protic solvent; (c) Transition metal salt selected from the groupconsisting of ytterbium, hafnium, scandium, neodynium, gadolium, andzirconium salts.
 63. A process according to claim 62 wherein thereaction is carried out at a temperature of from 15° C. to 65° C.